Binding function 3 (BF3) site compounds as therapeutics and methods for their use

ABSTRACT

This invention provides compound having a structure of Formulas: Uses of such compounds for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are also provide.

CROSS REFERENCE TO A RELATED APPLICATION

This application is a National Stage Application of International PatentApplication No. PCT/CA2015/000239, filed Apr. 9, 2015; which claims thebenefit of U.S. Provisional Patent Application Ser. No. 61/977,445,filed Apr. 9, 2014 and U.S. Provisional Application No. 62/084,451,filed Nov. 25, 2014; all of which are incorporated herein by referencein their entirety.

TECHNICAL FIELD

This invention relates to therapeutics, their uses and methods for thetreatment of various indications, including various cancers. Inparticular the invention relates to therapies and methods of treatmentfor cancers such as prostate cancer.

BACKGROUND

Androgens are known to mediate their effects through the androgenreceptor (AR). Androgens play a role in a wide range of developmentaland physiological responses, for example, male sexual differentiation,maintenance of spermatogenesis, and male gonadotropin regulation (R. K.Ross, G. A. Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N.Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol35, 355-361 (1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N.Tanji, K. Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Also,androgens are associated with the development of prostatecarcinogenesis. Induction of prostatic carcinogenesis in rodent modelshas been associated with androgens (R. L. Noble, Cancer Res 37,1929-1933 (1977); R. L. Noble, Oncology 34, 138-141 (1977)) and menreceiving androgens in the form of anabolic steroids are reported tohave a higher incidence of prostate cancer (J. T. Roberts & D. M.Essenhigh, Lancet 2, 742 (1986); J. A. Jackson, J. Waxman & A. M.Spiekerman, Arch Intern Med 149, 2365-2366 (1989); P. D. Guinan, W.Sadoughi, H. Alsheik, R. J. Ablin, D. Alrenga & I. M. Bush, Am J Surg131, 599-600 (1976)). Furthermore, prostate cancer does not develop ifhumans or dogs are castrated before puberty (J. D. Wilson & C.Roehrborn, J Clin Endocrinol Metab 84, 4324-4331 (1999); G. Wilding,Cancer Sury 14, 113-130 (1992)). Castration of adult males causesinvolution of the prostate and apoptosis of prostatic epithelium (E. M.Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000); J. T.Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgensprovides the underlying rationale for treating prostate cancer withchemical or surgical castration (i.e. androgen ablation).

Prostate cancer is the second leading cause of male cancer-related deathin Western countries (Damber, J. E. and Aus, G. Lancet (2008)371:1710-1721). Numerous studies have shown that the androgen receptor(AR) is central not only to the development of prostate cancer, but alsothe progression of the disease to the castration resistance state(Taplin, M. E. et al. J. Clin. Oncol. (2003) 21:2673-8; and Tilley, W.D. et al. Cancer Res. (1994) 54:4096-4102). Thus, effective inhibitionof human AR remains one of the most effective therapeutic approaches tothe treatment of advanced, metastatic prostate cancer.

The AR possesses a modular organization characteristic of all nuclearreceptors. It is comprised of an N-terminal domain, a central DNAbinding domain, a short hinge region, and C-terminal domain thatcontains a hormone ligand binding pocket and the Activation Function-2(AF2) site (Gao, W. Q. et al. Chem. Rev. (2005) 105:3352-3370). Thelatter represents a hydrophobic groove on the AR surface which isflanked with regions of positive and negative charges—“charge clamps”that are significant for binding AR activation factors (Zhou, X. E. etal. J. Biol. Chem. (2010) 285:9161-9171). Recent studies have identifieda novel site on the AR called Binding Function 3 (BF3) that is involvedinto AR transcriptional activity.

It has been proposed a small molecule bound to the BF3 site could causethe AR protein to undergo an allosteric modification that prevents ARinteractions with co-activators. Importantly, the BF3 site is locatednear, but distinct from, the ligand-binding site that is normallytargeted by conventional anti-androgen drugs. Chemicals such asflufenamic acid (FLUF), thriiodothyronine (T3) and 3,3′,5 triiodothyroacetic acid (TRIAC), can bind to the BF3 cleft, inhibit AF2interactions and interfere with AR activity (Estebanez-Perpina, E. etal. Proc Natl Acad Sci USA (2007) 104:16074-16079). While thesecompounds revealed the importance of the BF3 site, they have shown a lowpotency (IC₅₀>50 μM) and were found to bind non-specifically to the AR.

The activation of AR follows a well characterized pathway: in thecytoplasm, the receptor is associated with chaperone proteins thatmaintain agonist binding conformation of the AR (Georget, V. et al.Biochemistry (2002) 41:11824-11831). Upon binding of an androgen, the ARundergoes a series of conformational changes, disassociation fromchaperones, dimerization and translocation into the nucleus (Fang, Y. F.et al. J. Biol. Chem. (1996) 271:28697-28702; and Wong, C. I. et al. J.Biol. Chem. (1993) 268:19004-19012) where it further interacts withco-activator proteins at the AF2 site (Zhou, X. E. et al. J. Biol. Chem.(2010) 285:9161-9171). This event triggers the recruitment of RNApolymerase II and other factors to form a functional transcriptionalcomplex with the AR.

Notably, the current anti-androgens such as bicalutamide, flutamide,nilutamide and MDV₃₁₀₀, all target this particular process. However,instead of affecting the AR-cofactor interaction directly, theseanti-androgens act indirectly, by binding to the AR ligand binding site.Thus, by preventing androgens from binding they also preventconformational changes of the receptor that are necessary forco-activator interactions. While treatment with these AR inhibitors caninitially suppress the prostate cancer growth, long term hormone therapybecomes progressively less effective (Taplin, M. E. et al. J. Clin.Oncol. (2003) 21:2673-8; and Tilley, W. D. et al. Cancer Res. (1994)54:4096-4102). Factors that make the AR less sensitive to conventionalanti-androgens include resistance mutations at the ligand binding sitethat can even lead AR antagonists to act as agonists furthercontributing to cancer progression (Chen, Y. et al. Lancet Oncol. (2009)10:981-991).

Androgens also play a role in female cancers. One example is ovariancancer where elevated levels of androgens are associated with anincreased risk of developing ovarian cancer (K. J. Helzlsouer, et al.,JAMA 274, 1926-1930 (1995); R. J. Edmondson, et al, Br J Cancer 86,879-885 (2002)). The AR has been detected in a majority of ovariancancers (H. A. Risch, J Natl Cancer Inst 90, 1774-1786 (1998); B. R. Rao& B. J. Slotman, Endocr Rev 12, 14-26 (1991); G. M. Clinton & W. Hua,Crit Rev Oncol Hematol 25, 1-9 (1997)), whereas estrogen receptor-alpha(ERa) and the progesterone receptor are detected in less than 50% ofovarian tumors.

SUMMARY

This invention is based in part on the fortuitous discovery thatcompounds described herein modulate androgen receptor (AR) activity.Specifically, compounds identified herein, show inhibition of AndrogenReceptor Binding Function-3 (BF3).

In accordance with a first aspect, there is provided a method ofmodulating AR activity, the method comprising administering a compoundhaving the structure of Formula I:

wherein,

is either a single or a double bond between D₂ and D₃;

A₁ may be H, CH₃, CH₂CH₃, OH, CH₂OH, OCH₃,

Alternatively A₁ may be F, Br or Cl, provided that D₃ is not

A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃,

or ═O;

A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

I, OH,

or ═O;

A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃,

or ═O;

wherein

E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, are each independently CH or N;

E₂, E₃, E₄, E₅, and E₆, are each independently H, OH,

Br, Cl, F, I, or CH₃;

E₇ is CH₂, O, NH, or C═O;

E₉, E₁₀, E₁₁, E₁₂, and E₁₃, are each independently H,

OH, Br, Cl, F, I, or CH₃;

E₁₅ is CH₂, O, NH, or C═O;

E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, are each independently H,

OH, Br, Cl, F, I, or CH₃;

E₂₃ is CH, CH₂, O, N, NH, or C═O;

where

is either a single or a double bond between E₂₂ and E₂₃;

E₂₄ is CH₂, O, NH, or C═O;

E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, are each independently H,

OH, Br, Cl, F, I, or CH₃;

E₃₁ is N, CH, CBr, CCl, CF, COH, C═O, or CCH₃;

E₃₂ is NH, CH₂, O, or S;

E₃₃, E₃₄, E₃₅, and E₃₆, are each independently H, OH

Br, Cl, F, I, or CH₃;

E₃₇ is S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃,

N-E₃₈, CH-E₃₉,

E₃₈ is NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃,C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃,C(O)—CH₂—CH₂—CH₃, C(O)—O—CH₂—CH₃, or;

E₃₉ is CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O,CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃,C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, orC(O)—O—CH₂—CH₃;

E₄₀ is CH₃, CH₂—CH₃, CH₂N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O,CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃,C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, orC(O)—O—CH₂—CH₃;

E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, are each independently H,

OH, Br, Cl, F, I, or CH₃;

D₂ is

G₁ is CH, N, CCH₃, CH₂,

O, S, or NH;

G₂ is C, CH, or N;

G₃ is CH,

CH₂, or N;

G₄ is

G₅, G₆, and G₇, are each independently H, OH, Br, Cl, F, I, or CH₃;

G₈ is NH, CH₂, O, or S;

G₉, G₁₀, G₁₁, and G₁₂, are each independently H, OH, Br, Cl, F, I, orCH₃;

G₁₃ is C, CH, or N;

G₁₄ is C═O, CH₂, or NH;

G₁₅ is C═O, CH₂, or NH;

G₁₆ is

G₁₇, G₁₈, G₁₉, G₂₀, and G₂₁, are each independently H, OH, Br, Cl, F, I,or CH₃, provided that if G₁₇ is OH, then one or more of G₁₈, G₁₉, G₂₀,and G₂₁ are selected from OH, Br, Cl, F, I, or CH₃;

G₂₂ is NH, CH₂, O, or S;

G₂₃, G₂₄, G₂₅, and G₂₆, are each independently H, OH, Br, Cl, F, I, orCH₃;

G₂₇ is C, CH, CCH₃, CC(O)OCH₂CH₃, or N;

G₂₈ is C, CH, or N;

G₂₉ is CH, CH₂, C═O, CCH₃, or N;

where

is either a single or a double bond between G₂₈ and G₂₉;

G₃₀ is CH₂, N—N═O, NCH₃, NCH₂CH₂OH, CH—N═O, CHCH₃, CHCH₂CH₂OH, S, O,

or NH;

G₃₁, G₃₂, and G₃₃, are each independently H, OH, NH₂, Br, Cl, F, I,

OCH₃,

CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N;

G₃₄, is H, OH, NH₂,

OCH₃, CH₃, CH₂OH, I or absent when G₃₅ is N;

G₃₅, G₃₆, G₃₇, and G₃₈, are each independently C or N;

G₃₉ is C, CH, or N;

G₄₀ is CH, or N;

G₄₁ is NH, S, O, or CH₂;

G₄₂, G₄₃, G₄₄, and G₄₅, are each independently H, OH, Br, Cl, F, I, orCH₃;

G₄₆ is C, CH, or N;

G₄₇, G₄₈, G₅₀, and G₅₁, are each independently H, OH, Br, Cl, F, I, orCH₃;

G₄₉ is OH, Br, Cl, F, I or CH₃;

G₅₂ is C; CH, or N;

G₅₃ is CH₂, NH, S, or O;

G₅₄, G₅₅; G₅₆; G₅₇; and G₅₈; are each independently H, OH, Br, Cl, F, I,or CH₃;

D₃ may be

D₃ may be

Alternatively, D₃ may be

provided that A₁ is H, CH₃, F, Cl or Br and A₂ is H, CH₃, NH₂, OH orOCH₃, A₃ is H, F, Cl or Br and A₄ is H, F, Cl or Br.Alternatively, D₃ may be

provided A₁ is CH₃, A₂ is F, A₃ is H and A₄ is H.Alternatively, D₃ may be

provided that at least one of A₁, A₃ or A₄ is F, Cl or Br and A₂ is H,CH₃, NH₂, OH or OCH₃.Alternatively, D₃ may be

provided that at least one of A₂ or A₃ is F, Cl or Br.Alternatively, D₃ may be

provided that A₄ is H.Alternatively, D₃ may be

provided that A₁ is CH₃.Alternatively, D₃ may be

provided that at least one of A₁ or A₂ is F, Cl, Br or CH₃.Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₃ is F, Cl or Br.Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₁ is H, OH, CH₂OH,

CF₃, F, Cl or Br, A₃ is H, Br, NH₂, F, Cl, OCH₃,

CF₃, I, OH,

or ═O and A₄ is H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃,

CF₃,

or ═O.Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₁ is not CH₃.Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then A₁ is not CH₃.Alternatively, D₃ may be

provided that if A₂ is F, Cl or Br then at least one or both of A₁ andA₃ are F, Cl or Br.Alternatively, D₃ may be

provided that if A₁ is CH₃ then A₂ is not F, Br or Cl.Alternatively, D₃ may be

provided that if A₁ is CH₃ then A₂ is H.Alternatively, D₃ may be

provided that A₁ is F, Br or Cl.Alternatively, D₃ is

provided that A₁-A₄ are all H.Alternatively, D₃ may be

provided that if A₄ is CH₃, then A₁ is CH₂OH,

CF₃, F, Cl or Br, A₂ is Br, NH₂, F, Cl,

CF₃, I or

and A₃ is Br, Cl, F, I, CH₃, NH₂,

or ═O.Alternatively, D₃ may be

provided that A₄ is H, and A₁₋₄ are independently selected from Br, Cl,F, I, CH₃, NH₂,

CF₃,

or ═O.Alternatively, D₃ may be

provided that A₁ is F and A₃ is F.Alternatively, D₃ may be

provided that A₁ is F, Cl or Br and A₃ is F, Cl or Br.Alternatively, D₃ may be

provided that A₁ is F, A₃ is F and A₄ is F.Alternatively, D₃ may be

provided that A₁ is F, Cl or Br, A₃ is F, Cl or Br and A₄ is F, Cl orBr.Alternatively, D₃ may be

provided that A₁ is F, Cl or Br, A₃ is F, Cl or Br and A₄ is F, Cl orBr.Alternatively, D₃ is

provided that A₂ is H, if A₁ is CH₃.

J₁ is CH, N, CCH₃, CH₂, NCH₃, CN═O, C═O,

N—CH₂—CH₂—CH₃, CH═O, N—N═O,

NCH₂C(O)OCH₂CH₃, N—CH₂—C(O)—O—CH₂—CH₃, O, S, or NH.

J₂ is CH, C, or N.

J₃ is C═S, C═O, NH, or CH₂.

J₄ is CH or N;

J₅ is CH₂, NH, S or O;

J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ are each independently H, OH, Br,Cl, F, I, or CH₃;

J₁₄ is CH, C, or N;

J₁₅ is C═S, C═O, NH, or CH₂;

J₁₆, J₁₇, J₁₈, J₁₉; and J₂₀ are each independently H, OH, Br, Cl, F, I,

or CH₃;

J₂₁ is CH, C, or N;

J₂₂ is CH₂, or NH;

J₂₃ is CH, or N;

J₂₄, J₂₅, J₂₆, and J₂₇ are each independently H, OH, Br, Cl, F, I, orCH₃;

J₂₈ is CH, C, or N;

J₃₁ is H, OH, Br, F, I, C(O)NH₂, OCH₃, or CH₃;

J₂₉, J₃₀, J₃₂, and J₃₃ are each independently H, OCH₃, OH, Br, Cl, F, I,C(O)NH₂, CF₃,

NH₂, or CH₃;

J₃₄ is CH, C, or N;

J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ are each independently H, OCH₃, OH, Br, Cl,F, I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₄₀ is CH, C, or N;

J₄₁ is H, OH, Br, Cl, F, I, NH₂, or CH₃, or

J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ are each independently H, OH, Br, Cl, F, I,NH₂, or CH₃;

J₄₇ is CH, C, or N;

J₄₈ is S, CH₂, C═O, O, or NH;

J₄₉ is CH₂, C═O, S, O, or NH;

J₅₅ is C, or N;

J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, are each independently H, OH, NH₂, Br, Cl,F, I,

OCH₃, CF₃, CH₃ or is absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N;

J₅₆ is CH, C, or N;

J₅₇ is N, or CH;

J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, are each independently H, OH, NH₂, Br, Cl,F, I,

OCH₃, CF₃, or CH₃;

J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, are each independently H, OH, NH₂, Br, Cl,F, I,

OCH₃, CF₃, or CH₃;

J₆₃ is CH, C, or N;

J₆₄ is CH, CH₂, NH, CN═O, C═O, O, CCH₃, NCH₃, NC(O)OCH₃,

or N;

J₆₅ is CH₂, NH, C═O, O, S, NN═O, NCH₃, NC(O)OCH₃,

J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, OH, Br, Cl, F,I, C(O)NH₂,

NH₂, or CH₃;

J₇₀ is CH, C, or N;

J₇₁, J₇₂, J₇₃, and J₇₄ may each independently be H, OCH₃, OH, Br, Cl, F,I, C(O)NH₂, CF₃,

NH₂, or CH₃;

J₇₅ may be CH, or N;

J₇₇ is

and

provided that one or more of D₁-D₃ links to at least one ring inaddition to the bicyclic structure of Formula I. For example, compounds13720-13726, do not link to at least one ring in addition to thebicyclic structure of Formula I, whereas, for example, 13566 and 13742do link to at least one ring in addition to the bicyclic structure ofFormula I.

In accordance with a further aspect, there is provided a use of acompound having the structure of Formula I as described herein formodulating AR activity.

In accordance with a further aspect, there is provided a use of acompound having the structure of Formula I as described herein for themanufacture of a medicament for modulating AR activity.

A₁ may be H, CH₃, CH₂CH₃, OH, CH₂OH, OCH₃,

or CF₃. Alternatively A₁ may be F, Br or Cl, provided that D₃ is not

A₁ may be H, CH₃, OH, CH₂OH, OCH₃,

or CF₃. A₁ may be H, CH₃, OH, CH₂OH, OCH₃,

A₁ may be H, CH₃, OH, CH₂OH, or OCH₃. A₁ may be H, CH₃, OH, CH₂OH, or

A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃,

CF₃,

or ═O. A₂ may be H, Br, OH, Cl, or

A₂ may be H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃ or ═O. A₂ may be H, Br,OH, Cl, F, I, CH₃, NH₂ or OCH₃. A₂ may be H, Br, OH, or Cl. A₂ may be H,Br, OH, Cl, or F.A₃ may be H, Br, NH₂, F, Cl, OCH₃,

CF₃, I, OH,

or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃,

or CF₃. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃, OH or ═O. A₃ may be H,Br, NH₂, F, Cl, OCH₃, CH₃,

CF₃, or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃,

CF₃, OH or ═O. A₃ may be H, Br, NH₂, F, Cl, OCH₃, CH₃, OH or ═O. A₃ maybe H, Br, NH₂, F, Cl, OCH₃, or CH₃.A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃,

CF₃,

be H, Br. A₄ may be H, Br, Cl, F, I, CH₃, NH₂, OH, OCH₃ or ═O. A₄ may beH, Br, C, F, CH₃, NH₂, OH, OCH₃, or ═O. A₄ may be H, Br, Cl, F, I, CH₃,NH₂, OH or OCH₃. A₄ may be H, Br, Cl, CH₃, NH₂, OH, OCH₃,

CF₃,

or ═O.D₁ may be

E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, may each independently be CH or N.E₁, E₈, E₁₄, E₁₆, E₂₂, E₃₀, and E₄₁, may be N. E₁, E₈, E₁₄, E₁₆, E₂₂,E₃₀, and E₄₁, may be CH.E₂, E₃, E₄, E₅, and E₆, may each independently be H, OH,

Br, Cl, F, I, or CH₃. E₂, E₃, E₄, E₅, and E₆, may each independently beH, OH, or

E₂, E₃, E₄, E₅, and E₆, may each independently be H or OH.E₇ may be CH₂, O, NH, or C═O. E₇ may be CH₂. E₇ may be CH₂, O or C═O. E₇may be CH₂ or O. E₇ may be CH₂, O, NH or C═O. E₇ may be CH₂, NH or C═O.E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H,

OH, Br, Cl, F, I or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may eachindependently be H orE₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H, OH, Br, Cl, F,I or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may each independently be H,

OH, Br, Cl, F, or CH₃. E₉, E₁₀, E₁₁, E₁₂, and E₁₃, may eachindependently be H, OH, or CH₃. E₉, E₁₀, E₁₂, and E₁₃, may eachindependently be H or CH₃.

E₁₅ may be CH₂, O, NH or C═O. E₁₅ may be NH. E₁₅ may be CH₂, O or NH.E₁₅ may be O, NH, or C═O. E₁₅ may be NH or C═O.

E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may each independently be H,

OH, Br, Cl, F, I, or CH₃. E₁₇, E₁₈, E₁₉, E₂₀, and E₂₁, may eachindependently be H, OH, Br, Cl, F, I or CH₃. E₁₇, E₁₈, E₁₉, E₂₀, andE₂₁, may each independently be H, Cl, or CH₃. E₁₇, E₁₈, E₁₉, E₂₀, andE₂₁, may each independently be H, OH, Br, Cl, F or CH₃.E₂₃ may be CH, CH₂, O, N, NH, or C═O. E₂₃ may be N. E₂₃ may be O, N, NH,or C═O. E₂₃ may be CH, CH₂, O, N or NH. E₂₃ may be N or NH.E₂₄ may be CH₂, O, NH, or C═O. E₂₄ may be NH. E₂₄ may be CH₂, NH, orC═O. E₂₄ may be O or NH. E₂₄ may be CH₂, O or NH. E₂₄ may be NH, or C═O.E₂₄ may be CH₂ or NH.E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may each independently be H,

OH, Br, Cl, F, I, or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, may eachindependently be H, OH, Br, Cl, F, I or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, andE₂₉, may each independently be H or Cl. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉, mayeach independently be H, OH, Br, Cl, F, or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, andE₂₉, may each independently be H, OH, Cl or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, andE₂₉, may each independently be H or CH₃. E₂₅, E₂₆, E₂₇, E₂₈, and E₂₉,may each independently be H, Br, Cl or CH₃.E₃₁ may be N, CH, CBr, CCl, CF, COH, C═O, or CCH₃. E₃₁ may be N. E₃₁ maybe N, CH, COH, C═O, or CCH₃. E₃₁ may be N, CH, CCl, COH, C═O, or CCH₃.E₃₁ may be N, CH, COH or CCH₃.E₃₂ may be NH, CH₂, O, or S. E₃₂ may be NH or O. E₃₂ may be NH, CH₂ orO. E₃₂ may be NH. E₃₂ may be O. E₃₂ may be NH, O or S.E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH,

Br, Cl, F, I, or CH₃. E₃₃, E₃₄, E₃₅, and E₃₆, may each independently beH, OH, Br, Cl, F, I or CH₃.E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH,

or CH₃. E₃₃, E₃₄, E₃₅, and E₃₆, may each independently be H, OH or CH₃.E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃,

N-E₃₈, CH-E₃₉,

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃ or

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, N—CH₂—C(O)—O—CH₂—CH₃,

E₃₇ may be S, O, NH, CH₂, NCH₃,

C═O, N—N═O, N—CH₂—CH₂—OH, or N—CH₂—C(O)—O—CH₂—CH₃.E₃₈ may be NH₂, O—CH₃, O—NH₂, CH₂—N═O, CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃,C—O—CH₃, C(O)—O—CH₃, C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃,C(O)—CH₂—CH₂—CH₃, C(O)—O—CH₂—CH₃, or

E₃₈ may be NH₂, O—CH₃ or O—NH₂. E₃₈ may be NH₂ or O—CH₃.E₃₉ may be CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O,CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃,C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃ or C(O)—O—CH₂—CH₃.E₃₉ may be CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O,or CH₂—CH₃. E₃₉ may be CH₃, CH₂—CH₃, OH, OOH, NH₂, O—CH₃, O—NH₂, C—O—CH₃or C(O)—O—CH₃.E₄₀ may be CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃, O—NH₂, CH₂—N═O,CH₂—CH₃, N(H)OH, C(O)—O—CH₂—CH₃, C—O—CH₃, C(O)—O—CH₃,C(O)—O—CH₂—CH₂—CH₃, C—O—CH₂—CH₂—CH₃, C(O)—CH₂—CH₂—CH₃, orC(O)—O—CH₂—CH₃. E₄₀ may be CH₃, CH₂—CH₃, CH₂—N═O, OH, OOH, NH₂, O—CH₃ orO—NH₂.E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may each independently be H,

OH, Br, Cl, F, I or CH₃. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may eachindependently be H, OH, Cl, or CH₃. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, mayeach independently be H or Cl. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may eachindependently be H, Cl, or CH₃. E₄₂, E₄₃, E₄₄, E₄₅, and E₄₆, may eachindependently be H, OH or Cl.D₂ may be

D₂ may be

D₂ may be

G₁ may be CH, N, CCH₃, CH₂,

O, S, or NH. G, may be CH, N, CCH₃, CH₂, or

G₁ may be CH, N, CCH₃, CH₂,

G₁ may be CH, N, CCH₃, CH₂, O, S, or NH. G, may be CH, N, CCH₃ or CH₂.G₂ may be C, CH, or N. G₂ may be C. G₂ may be C. G₂ may be C or CH. G₂may be C or N. G₃ may be CH,

CH₂, or N. G₃ may be CH,

G₃ may be CH, CH₂ or N. G₃ may be CH.G₄ may be

G₄ may be

G₄ may be

G₅, G₆, and G₇, may each independently be H, OH, Br, Cl, F, I, or CH₃.G₅, G₆, and G₇, may each independently be H or CH₃. G₅, G₆, and G₇, mayeach independently be H, OH, or CH₃. G₅, G₆, and G₇, may eachindependently be H, Br, Cl, F, or CH₃. G₅, G₆, and G₇, may eachindependently be H, OH, Br, CH₃.G₈ may be NH, CH₂, O, or S. G₈ may be NH. G₈ may be NH, O, or S. G₈ maybe NH, CH₂, or S. G₈ may be NH or S. G₈ may be NH or CH₂.G₉, G₁₀, G₁₁, and G₁₂, may each independently be H, OH, Br, Cl, F, I orCH₃. G₉, G₁₀, G₁₁, and G₁₂, may each independently be H or Br. G₉, G₁₀,G₁₁, and G₁₂, may each independently be H, OH, Br, Cl or F. G₉, G₁₀,G₁₁, and G₁₂, may each independently be H, OH, Br, Cl, F or CH₃. G₉,G₁₀, G₁₁, and G₁₂, may each independently be H, OH or Br.G₁₃ may be C, CH, or N. G₁₃ may be C or N. G₁₃ may be N. G₁₃ may be C.G₁₄ may be C═O, CH₂, or NH. G₁₄ may be NH. G₁₄ may be CH₂. G₁₄ may beNH.G₁₅ may be C═O, CH₂, or NH. G₁₅ may be C═O. G₁₅ may be CH₂. G₁₅ may beNH.G₁₆ may be

G₁₆ may be

G₁₆ may be

G₁₇, G₁₈, G₁₉, G₂₀, and G₂₁, are each independently H, OH, Br, Cl, F, I,or CH₃, provided that if G₁₇ is OH, then one or more of G₁₈, G₁₉, G₂₀,and G₂₁ are selected from OH, Br, Cl, F, I, or CH₃.G₂₂ may be NH, CH₂, O, or S. G₂₂ may be NH. G₂₂ may be NH or S. G₂₂ maybe NH, O or S. G₂₂ may be NH or CH₂. G₂₂ may be NH, O, or S. G₂₂ may beNH or O.G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, OH, Br, Cl, F, I orCH₃. G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H or Br. G₂₃,G₂₄, G₂₅, and G₂₆, may each independently be H, OH, Br, Cl, F, or CH₃.G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, Br, Cl, F or I.G₂₃, G₂₄, G₂₅, and G₂₆, may each independently be H, OH, Br or CH₃.G₂₇ may be C, CH, CCH₃, CC(O)OCH₂CH₃, or N. G₂₇ may be C, CH, CCH₃ orCC(O)OCH₂CH₃. G₂₇ may be C. G₂₇ may be CH. G₂₇ may be CCH₃. G₂₇ may beCC(O)OCH₂CH₃.G₂₈ may be C, CH, or N. G₂₈ may be C or N. G₂₈ may be C. G₂₈ may be N.G₂₉ may be CH, CH₂, C═O, CCH₃, or N. G₂₉ may be CH. G₂₉ may be CH₂. G₂₉may be C═O, CCH₃.G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH, CH—N═O, CHCH₃, CHCH₂CH₂OH, S, O,

or NH. G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH,

or NH. G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH, CH—N═O, CHCH₃,CHCH₂CH₂OH, S, O, or NH. G₃₀ may be CH₂, N—N═O, NCH₃, NCH₂CH₂OH, or NH.G₃₁, G₃₂, and G₃₃, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N. G₃₁, G₃₂,and G₃₃, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃, CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N. G₃₁, G₃₂,and G₃₃, may each independently be H, OH, NH₂, Br, Cl, F, OCH₃, CH₃,CH₂OH, or absent when G₃₆, G₃₇, or G₃₈ is N.G₃₄, may be H, OH, NH₂,

OCH₃, CH₃, CH₂OH, I or absent when G₃₅ is N. G₃₄, may be H, OH, NH₂,

OCH₃, CH₃, CH₂OH, or absent when G₃₅ is N. G₃₄, may be H, OH, NH₂, OCH₃,CH₃, CH₂OH, or absent when G₃₅ is N.G₃₅, G₃₆, G₃₇, and G₃₈, may each independently be C or N. G₃₅, G₃₆, G₃₇,and G₃₈, may each be N. G₃₅, G₃₆, G₃₇, and G₃₈, may each be C.G₃₉ may be C, CH or N. G₃₉ may be C. G₃₉ may be C or CH. G₃₉ may be C orN. G₄₀ may be CH, or N. G₄₀ may be N. G₄₀ may be CH.G₄₁ may be NH, S, O, or CH₂. G₄₁ may be NH, S or O. G₄₁ may be NH. G₄₁may be S.G₄₂, G₄₃, G₄₄, and G₄₅, may each independently be H, OH, Br, Cl, F, I orCH₃. G₄₂, G₄₃, G₄₄, and G₄₅, may each independently be H or Br. G₄₂,G₄₃, G₄₄, and G₄₅, may each independently be H, OH, Br or CH₃.G₄₆ may be C, CH, or N. G₄₆ may be C. G₄₆ may be C or N. G₄₆ may be CHor N.G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be H, OH, Br, Cl, F, I orCH₃. G₄₇, G₄₈, G₅₀, and G₅₁, are each independently be H or OH. G₄₇,G₄₈, G₅₀, and G₅₁, are each independently be H, OH or CH₃. G₄₇, G₄₈,G₅₀, and G₅₁, are each be H. G₄₇, G₄₈, G₅₀, and G₅₁, are eachindependently be OH. G₄₉ is OH, Br, Cl, F, I or CH₃. G₄₉ is Br, Cl, F orI. G₄₉ is OH or CH₃.G₅₂ may be C, CH or N. G₅₂ may be C. G₅₂ may be C or N. G₅₂ may be C orCH.G₅₃ may be CH₂, NH, S or O. G₅₃ may be NH. G₅₃ may be CH₂ or NH. G₅₃ maybe NH or O. G₅₃ may be NH or S.G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each independently be H, OH, Br, Cl, F,I or CH₃. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each independently be H, Clor F. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each be H. G₅₄, G₅₅, G₅₆, G₅₇,and G₅₈, may each be Cl. G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each be F.G₅₄, G₅₅, G₅₆, G₅₇, and G₅₈, may each independently be H, Br, Cl, F orCH₃.D₃ may be

D₃ may be

D₃ may be

J₁ may be CH, N, CCH₃, CH₂, NCH₃, CN═O, C═O,

N—CH₂—CH₂—CH₃, CH═O, N—N═O,

NCH₂C(O)OCH₂CH₃, N—CH₂—C(O)—O—CH₂—CH₃, O, S or NH. J₁ may be CH, N, CH₂,NCH₃, CN═O, C═O,

or NH. J₁ may be CH, N, CCH₃, CH₂, NCH₃, CN═O, C═O,

O, S or NH. J₂ may be CH, C, or N. J₂ may be CH. J₂ may be CH or C. J₂may be CH, or N. J₃ may be C═S, C═O, NH, or CH₂. J₃ may be C═S. J₃ maybe C═S or CH₂. J₃ may be C═S or C═O. J₃ may be C═S or NH. J₄ may be CHor N. J₄ may be N. J₄ may be CH. J₅ may be CH₂, NH, S or O. J₅ may be O.J₅ may be CH₂ or O. J₅ may be NH, S or O. J₅ may be S or O. J₅ may be NHor O. J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ may each independently beH, OH, Br, Cl, F, I or CH₃. J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ mayeach independently be H. J₆, J₇, J₈, J₉, J₁₀, J₁₁, J₁₂, and J₁₃ may eachindependently be H, OH, Br, Cl, F or CH₃. J₁₄ may be CH, C, or N. J₁₄may be N. J₁₄ may be CH or N. J₁₄ may be C or N. J₁₅ may be C═S, C═O, NHor CH₂. J₁₅ may be CH₂. J₁₅ may be NH or CH₂. J₁₅ may be C═S or CH₂. J₁₅may be C═O or CH₂.J₁₆, J₁₇, J₁₈) J₁₉, and J₂₀ may each independently be H, OH, Br, Cl, F,I,

or CH₃. J₁₆, J₁₇, J₁₈, J₁₉, and J₂₀ may each independently be H or

J₁₆, J₁₇, J₁₈, J₁₉, and J₂₀ may each independently be H, OH, Br, Cl, F,

or CH₃. J₂₁ may be CH, C or N. J₂, may be CH. J₂₁ may be CH or N. J₂₁may be CH or C. J₂₂ may be NH. J₂₂ may be CH₂. J₂₂ may be CH₂ or NH. J₂₃may be CH or N. J₂₃ may be CH. J₂₃ may be N. J₂₄, J₂₅, J₂₆, and J₂₇ mayeach independently be H, OH, Br, Cl, F, I or CH₃. J₂₄, J₂₅, J₂₆, and J₂₇may each independently be H. J₂₄, J₂₅, J₂₆, and J₂₇ may eachindependently be H, OH or CH₃. J₂₄, J₂₅, J₂₆, and J₂₇ may eachindependently be H, OH, Br, Cl or CH₃. J₂₈ may be CH, C or N. J₂₈ may beC. J₂₈ may be CH or C. J₂₈ may be C or N. J₃₁ may be H, OH, Br, F, I,C(O)NH₂, OCH₃ or CH₃. J₃₁ may be H, Br, OCH₃ or CH₃. J₃₁ may be H, OH,Br, Cl, F, I, C(O)NH₂, OCH₃ or CH₃. J₃₁ may be Cl. J₃₁ may be H. J₃₁ maybe Br. J₃₁ may be OCH₃. J₃₁ may be CH₃. J₂₉, J₃₀, J₃₂, and J₃₃ may eachindependently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₂₉, J₃₀, J₃₂, and J₃₃ may each independently be H, OH, Br,Cl, C(O)NH₂, CF₃ or CH₃. J₂₉, J₃₀, J₃₂, and J₃₃ may each independentlybe H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, NH₂, or CH₃. J₃₄ may be CH, C, orN. J₃₄ may be C. J₃₄ may be CH or C. J₃₄ may be C or N. J₃₅, J₃₆, J₃₇,J₃₈, and J₃₉ may each independently be H, OCH₃, OH, Br, Cl, F, I,C(O)NH₂, CF₃,

NH₂, or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H, Clor CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H, OCH₃,OH, Br, Cl, F, NH₂ or CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each be H, Clor CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be H. J₃₅,J₃₆, J₃₇, J₃₈, and J₃₉ may each independently be Cl. J₃₅, J₃₆, J₃₇, J₃₈,and J₃₉ may each independently be CH₃. J₃₅, J₃₆, J₃₇, J₃₈, and J₃₉ mayeach independently be CF₃. J₄₀ may be CH, C, or N. J₄₀ may be C. J₄₀ maybe CH or C. J₄₀ may be C or N. J₄₁ may be H, OH, Br, Cl, F, I, NH₂, CH₃or

J₄₁ may be H. J₄₁ may be H, OH, Br, Cl, F, NH₂ or CH₃. J₄₂, J₄₃, J₄₄,J₄₅, and J₄₆ may each independently be H, OH, Br, Cl, F, I, NH₂ or CH₃.J₄₂, J₄₃, J₄₄, J₄₅, and J₄₆ may each independently be H. J₄₂, J₄₃, J₄₄,J₄₅, and J₄₆ may each independently be H, OH, NH₂, or CH₃. J₄₂, J₄₃,J₄₄, J₄₅, and J₄₆ may each independently be H, OH, Br, Cl, NH₂ or CH₃.J₄₇ may be CH, C or N. J₄₇ may be C. J₄₇ may be CH, C or N. J₄₇ may beCH or C. J₄₇ may be C or N. J₄₈ may be S, CH₂, C═O, O, or NH. J₄₈ may beS, CH₂ or NH. J₄₈ may be S. J₄₈ may be CH₂. J₄₈ may be NH. J₄₉ may beCH₂, C═O, S, O, or NH. J₄₉ may be CH₂ or C═O. J₄₉ may be S, O, or NH.J₄₉ may be CH₂, C═O or NH. J₄₉ may be CH₂, C—O or S. J₄₉ may be CH₂, C═Oor O. J₅₅ may be C, or N. J₅₅ may be C. J₅₅ may be N. J₅₀, J₅₁, J₅₂,J₅₃, and J₅₄, may each independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, CH₃ or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N.J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each independently be H, OH, Br, F, CH₃or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂,J₅₃, and J₅₄, may each be H or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, orJ₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be OH or may be absentwhen J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, mayeach be Br or may be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₀,J₅₁, J₅₂, J₅₃, and J₅₄, may each be F or may be absent when J₅₀, J₅₁,J₅₂, J₅₃, or J₅₄ is N. J₅₀, J₅₁, J₅₂, J₅₃, and J₅₄, may each be CH₃ ormay be absent when J₅₀, J₅₁, J₅₂, J₅₃, or J₅₄ is N. J₅₆ may be CH, C orN. J₅₆ may be C. J₅₆ may be CH or C. J₅₆ may be C or N. J₅₇ may be N orCH. J₅₇ may be CH. J₅₇ may be N. J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, may eachindependently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃, or CH₃. J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, may each independentlybe H, F or CF₃, J₅₈, J₅₉, J₆₀, J₆₁, and J₆₂, may each independently beH, OH, NH₂, Br, Cl, F, I, OCH₃ or CH₃. J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, mayeach independently be H, OH, NH₂, Br, Cl, F, I,

OCH₃, CF₃ or CH₃. J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, may each independently beH, F or CF₃, J₆₃, J₆₄, J₆₅, J₆₆, and J₆₇, may each independently be H,OH, NH₂, Br, Cl, F, OCH₃ or CH₃, J₆₃ may be CH, C, or N. J₆₃ may be C orN. J₆₃ may be C. J₆₃ may be N. J₆₃ may be CH, CH₂, NH, CN═O, C═O, O,NCH₃, NC(O)OCH₃,

or N. J₆₄ may be CH, CH₂, NH, CN═O, C═O, O, CCH₃, NCH₃, NC(O)OCH₃,

or N. J₆₄ may be CH, CH₂, NH, CN═O, C═O, O, NCH₃, NC(O)OCH₃,

or N. J₆₅ may be CH₂, NH, C═O, O, S, NN═O, NCH₃, NC(O)OCH₃,

J₆₅ may be CH₂, NH, C═O, O, NN═O, NCH₃, NC(O)OCH₃,

J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, OH, Br, Cl, F,I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃,Br or CF₃. J₆₆, J₆₇, J₆₈, and J₆₉ may each independently be H, OCH₃, OH,Br, Cl, F, C(O)NH₂, NH₂ or CH₃. J₇₀ may be C. J₇₀ may be CH or C. J₇₀may be C or N. J₇₀ may be CH, C, or N. J₇₁, J₇₂, J₇₃, and J₇₄ may eachindependently be H, OCH₃, OH, Br, Cl, F, I, C(O)NH₂, CF₃,

NH₂, or CH₃. J₇₁, J₇₂, J₇₃, and J₇₄ may each independently be H, Br,CF₃, or CH₃. J₇₁, J₇₂, J₇₃, and J₇₄ may be H. J₇₁, J₇₂, J₇₃, and J₇₄ maybe Br. J₇₁, J₇₂, J₇₃, and J₇₄ may be CF₃. J₇₁, J₇₂, J₇₃, and J₇₄ may beCH₃. J₇₅ may be CH, or N. J₇₅ may be CH.J₇₇ may be

J₇₇ may be

One or more of D₁-D₃ links to at least one ring in addition to thebicyclic structure of Formula I.In accordance with a further aspect of the invention, there is provideda compound having the structure of Formula I as described herein, butprovided that the compound is not one of the compounds in TABLE 1.

TABLE 1 Known AR BF₃ Interactors. Internal External Number IdentifierSTRUCTURE 13312 ZINC 00298052

13309 ZINC 01234071

13310 ZINC 00297221

13232 ZINC 02992016

13050 ZINC 03365783

13300 ZINC 00270867

13299 ZINC 00499454

13304 ZINC 00270887

13258 ZINC 18191564

9125 ZINC 30469682

13186 ZINC 00513042

13224 ZINC 04106386

13250 ZINC 03149578

13303 ZINC 00270884

13257 ZINC 12345945

13243 ZINC 00253227

13424 ZINC 12346351

6054 ZINC 08718421

13029 ZINC 00210926

9128 ZINC 47424036

13216 ZINC 06025409

13260 ZINC 49491101

13416 ZINC 01869964

13411 ZINC 04106386

13214 ZINC 26472877

13235 ZINC 01037115

13127 ZINC 00392643

13261 ZINC 48546225

13215 ZINC 05504717

13167 NSC 105329

13206 ZINC 04962047

13145 ZINC 34603778

13245 ZINC 00555700

13036 ZINC 14961821

13166 ZINC 01723993

13164-B ZINC 02046058

13254 ZINC 18191551

13410 ZINC 04106383

13423 ZINC 18191568

13222 ZINC 02718340

13247 ZINC 48090221

13412 ZINC 02718340

13434 ZINC 00069102

13164-A ZINC 02046058

13220 ZINC 48544111

13225 ZINC 18191568

13436 ZINC 00068959

13255 ZINC 18191553

13163-A ZINC 02043019

13163-B ZINC 02043019

13256 ZINC 05848672

13427 ZINC 00588219

13259 ZINC 18191559

13226 ZINC 18191571

13562 Known see U.S. Pat. No. 6,207,679

13566 Known see U.S. Pat. No. 6,207,679

The compound may be selected from one or more of the active syntheticderivatives set out in TABLE 2.

TABLE 2 List of Active Synthetic AR BF₃ Interactor Derivatives InternalNumber STRUCTURE 9040

9034

13551

13550

9026

13544

13561

9028

9027

13538

13559

13512

13542

13524

13508

13530

13503

13502

9037

13543

13516

13505

13522

13548

13525

13532

13511

9043

13509

13510

13540

13560

13536

13556

13504

13549

13558

13535

13500

13552

13534

13537

13554

13541

13521

13506

13567

13568

13570

13569

13571

13573

13574

13576

13577

13579

13580

13582

13585

13587

13589

13591

13592

13593

13594

13595

13597

13600

13601

13602

13603

13606

13607

13610

13611

13612

13613

13614

13618

13619

13621

13622

13624

13625

13626

13627

13628

13629

13630

13633

13634

13639

13640

13641

13642

13643

13644

13645

13646

13650

13651

13652

13653

13654

13655

13656

13658

13660

13665

13674

13677

13680

13681

13682

13683

13684

13688

13691

13692

13693

13694

13695

13696

13697

13698

13699

13702

13704

13708

13710

13713

13717

13718

13719

13730

13731

13732

13733

13736

13738

13741

13742

13743

13744

13745

13749

13752

13753

13754

13755

13759

13760

13761

13762

13764

13766

13770

13771

13772

13773

13774

13775

13776

13782

13785

13786

13787

Alternatively, the compound may be selected from one or more of thefollowing:

The compound may have the structure of Formula III:

wherein,

R₁ is CH₃, OH, OCH₃, CH₂CH₃, or OCH₂CH₃;

R₂ is CH₃, OH, OCH₃, CH₂CH₃, or OCH₂CH₃;

or R₁ and R₂ form

M₁ is C or N;

M₂ is C or N;

Q₁ is H;

Q₂ is NH₂, Br, Cl, H, OCH₃, CH₂OH, OCH₂-Ph,

OH, F, I, C(O)NH₂,

NH₂, or CH₃;

Q₃ is NH₂, Br, Cl, H, OCH₃, CH₂OH, OCH₂-Ph,

OH, F, I, C(O)NH₂,

NH₂, or CH₃;

Q₄ is NH₂, Br, Cl, H, OCH₃, CH₂OH, OCH₂-Ph,

OH, F, I, C(O)NH₂,

NH₂, or CH₃; and

Q₅ is H, CH₃, CH₂CH₂OH,

OH, F, Br, Cl, I, or

The compound may be selected from one or more of the following:

The compound may be

The compound may be for use in the treatment of at least one indicationselected from the group including: prostate cancer, breast cancer,ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovariancysts, polycystic ovary disease, precocious puberty, and age-relatedmacular degeneration.The modulating AR activity is for the treatment of at least oneindication selected from the group including: prostate cancer, breastcancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism,ovarian cysts, polycystic ovary disease, precocious puberty, andage-related macular degeneration.The modulating AR activity may be for the treatment of prostate cancer.The mammalian cell may be a human cell. The cell may be a prostate cell.The cell may be a prostate cancer cell.The compound may be for use in the treatment of at least one indicationselected from the group consisting of: cancer, hair loss, acne,hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty,and age related macular degeneration. The cancer may be AR-mediatedcancer. The cancer may be selected from the group including of: prostatecancer, breast cancer, ovarian cancer, endometrial cancer and bladdercancer. The cancer may be Taxene resistant triple negative breastcancer.In accordance with a further aspect, there is provided a pharmaceuticalcomposition for modulating AR activity, the composition including acompound described herein, and a pharmaceutically acceptable carrier.In accordance with a further aspect, there is provided a method ofmodulating AR activity, the method including (a) administering acompound described herein or a pharmaceutical composition describedherein to a subject in need thereof.In accordance with a further aspect, there is provided a method formodulating AR activity, the method including administering to amammalian cell a compound or pharmaceutically acceptable salt thereof asdescribed herein.In accordance with a further aspect, there is provided a use of acompound described herein, for modulating AR activity.In accordance with a further aspect, there is provided a use of acompound described herein, for the manufacture of a medicament formodulating AR activity.In accordance with a further aspect, there is provided a pharmaceuticalcomposition including a compound or pharmaceutically acceptable saltthereof described herein and a pharmaceutically acceptable excipient.In accordance with a further aspect, there is provided a commercialpackage including (a) a compound described herein; and (b) instructionsfor the use thereof for modulating AR activity.In accordance with a further aspect, there is provided a commercialpackage including (a) a pharmaceutical composition comprising a compounddescribed herein and a pharmaceutically acceptable carrier; and (b)instructions for the use thereof for modulating AR activity.

DETAILED DESCRIPTION

The BF3 site is an attractive target for direct inhibition of the ARco-activation. In silico computational drug discovery methods were usedto conduct a virtual screen of ˜4 million purchasable lead-likecompounds from the ZINC database (Irwin, J. et al. Abstracts of PapersAm. Chem. Soc. (2005) 230:U1009) to identify potential BF3 binders. Thein silico methods included large-scale docking, in-site rescoring andconsensus voting procedures.

It will be understood by a person of skill that COOH and NR₂ may includethe corresponding ions, for example carboxylate ions and ammonium ions,respectively. Alternatively, where the ions are shown, a person of skillin the art will appreciate that the counter ion may also be present.

Those skilled in the art will appreciate that the point of covalentattachment of the moiety to the compounds as described herein may be,for example, and without limitation, cleaved under specified conditions.Specified conditions may include, for example, and without limitation,in vivo enzymatic or non-enzymatic means. Cleavage of the moiety mayoccur, for example, and without limitation, spontaneously, or it may becatalyzed, induced by another agent, or a change in a physical parameteror environmental parameter, for example, an enzyme, light, acid,temperature or pH. The moiety may be, for example, and withoutlimitation, a protecting group that acts to mask a functional group, agroup that acts as a substrate for one or more active or passivetransport mechanisms, or a group that acts to impart or enhance aproperty of the compound, for example, solubility, bioavailability orlocalization.

In some embodiments, compounds of Formula I or Formula II above may beused for systemic treatment of at least one indication selected from thegroup consisting of: prostate cancer, breast cancer, ovarian cancer,endometrial cancer, hair loss, acne, hirsutism, ovarian cysts,polycystic ovary disease, precocious puberty and age-related maculardegeneration. In some embodiments compounds of Formula I or Formula IImay be used in the preparation of a medicament or a composition forsystemic treatment of an indication described herein. In someembodiments, methods of systemically treating any of the indicationsdescribed herein are also provided.

Compounds as described herein may be in the free form or in the form ofa salt thereof. In some embodiment, compounds as described herein may bein the form of a pharmaceutically acceptable salt, which are known inthe art (Berge S. M. et al., J. Pharm. Sci. (1977) 66(1):1-19).Pharmaceutically acceptable salt as used herein includes, for example,salts that have the desired pharmacological activity of the parentcompound (salts which retain the biological effectiveness and/orproperties of the parent compound and which are not biologically and/orotherwise undesirable). Compounds as described herein having one or morefunctional groups capable of forming a salt may be, for example, formedas a pharmaceutically acceptable salt. Compounds containing one or morebasic functional groups may be capable of forming a pharmaceuticallyacceptable salt with, for example, a pharmaceutically acceptable organicor inorganic acid. Pharmaceutically acceptable salts may be derivedfrom, for example, and without limitation, acetic acid, adipic acid,alginic acid, aspartic acid, ascorbic acid, benzoic acid,benzenesulfonic acid, butyric acid, cinnamic acid, citric acid,camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid,diethylaceiic acid, digluconic acid, dodecylsulfonic acid,ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid,gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid,heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, 2-hydroxyethanesulfonic acid, isonicotinic acid, lacticacid, malic acid, maleic acid, malonic acid, mandelic acid,methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonicacid, p-toluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid,pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid,picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid,salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaricacid, thiocyanic acid or undecanoic acid. Compounds containing one ormore acidic functional groups may be capable of forming pharmaceuticallyacceptable salts with a pharmaceutically acceptable base, for example,and without limitation, inorganic bases based on alkaline metals oralkaline earth metals or organic bases such as primary amine compounds,secondary amine compounds, tertiary amine compounds, quaternary aminecompounds, substituted amines, naturally occurring substituted amines,cyclic amines or basic ion-exchange resins. Pharmaceutically acceptablesalts may be derived from, for example, and without limitation, ahydroxide, carbonate, or bicarbonate of a pharmaceutically acceptablemetal cation such as ammonium, sodium, potassium, lithium, calcium,magnesium, iron, zinc, copper, manganese or aluminum, ammonia,benzathine, meglumine, methylamine, dimethylamine, trimethylamine,ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine,tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,glucamine, methylglucamine, theobromine, purines, piperazine,piperidine, procaine, N-ethylpiperidine, theobromine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, morpholine, N-methylmorpholine,N-ethylmorpholine, dicyclohexylamine, dibenzylamine,N,N-dibenzylphenethylamine, i-ephenamine, N,N′-dibenzylethylenediamineor polyamine resins. In some embodiments, compounds as described hereinmay contain both acidic and basic groups and may be in the form of innersalts or zwitterions, for example, and without limitation, betaines.Salts as described herein may be prepared by conventional processesknown to a person skilled in the art, for example, and withoutlimitation, by reacting the free form with an organic acid or inorganicacid or base, or by anion exchange or cation exchange from other salts.Those skilled in the art will appreciate that preparation of salts mayoccur in situ during isolation and purification of the compounds orpreparation of salts may occur by separately reacting an isolated andpurified compound.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, polymorphs, isomeric forms) as described herein maybe in the solvent addition form, for example, solvates. Solvates containeither stoichiometric or non-stoichiometric amounts of a solvent inphysical association the compound or salt thereof. The solvent may be,for example, and without limitation, a pharmaceutically acceptablesolvent. For example, hydrates are formed when the solvent is water oralcoholates are formed when the solvent is an alcohol.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, isomeric forms) as described herein mayinclude crystalline and amorphous forms, for example, polymorphs,pseudopolymorphs, conformational polymorphs, amorphous forms, or acombination thereof. Polymorphs include different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability and/or solubility. Those skilled in the art willappreciate that various factors including recrystallization solvent,rate of crystallization and storage temperature may cause a singlecrystal form to dominate.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, polymorphs) as described herein includeisomers such as geometrical isomers, optical isomers based on asymmetriccarbon, stereoisomers, tautomers, individual enantiomers, individualdiastereomers, racemates, diastereomeric mixtures and combinationsthereof, and are not limited by the description of the formulaillustrated for the sake of convenience.

In some embodiments, pharmaceutical compositions as described herein maycomprise a salt of such a compound, preferably a pharmaceutically orphysiologically acceptable salt. Pharmaceutical preparations willtypically comprise one or more carriers, excipients or diluentsacceptable for the mode of administration of the preparation, be it byinjection, inhalation, topical administration, lavage, or other modessuitable for the selected treatment. Suitable carriers, excipients ordiluents (used interchangeably herein) are those known in the art foruse in such modes of administration.

Suitable pharmaceutical compositions may be formulated by means known inthe art and their mode of administration and dose determined by theskilled practitioner. For parenteral administration, a compound may bedissolved in sterile water or saline or a pharmaceutically acceptablevehicle used for administration of non-water soluble compounds such asthose used for vitamin K. For enteral administration, the compound maybe administered in a tablet, capsule or dissolved in liquid form. Thetablet or capsule may be enteric coated, or in a formulation forsustained release. Many suitable formulations are known, including,polymeric or protein microparticles encapsulating a compound to bereleased, ointments, pastes, gels, hydrogels, or solutions which can beused topically or locally to administer a compound. A sustained releasepatch or implant may be employed to provide release over a prolongedperiod of time. Many techniques known to one of sldll in the art aredescribed in Remington: the Science & Practice of Pharmacy by AlfonsoGennaro, 20^(th) ed., Lippencott Williams & Wilkins, (2000).Formulations for parenteral administration may, for example, containexcipients, polyalkylene glycols such as polyethylene glycol, oils ofvegetable origin, or hydrogenated naphthalenes. Biocompatible,biodegradable lactide polymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers may be used to control therelease of the compounds. Other potentially useful parenteral deliverysystems for modulatory compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes. Formulations for inhalation may contain excipients, forexample, lactose, or may be aqueous solutions containing, for example,polyoxyethylene-g-lauryl ether, glycocholate and deoxycholate, or may beoily solutions for administration in the form of nasal drops, or as agel.

Compounds or pharmaceutical compositions as described herein or for useas described herein may be administered by means of a medical device orappliance such as an implant, graft, prosthesis, stent, etc. Also,implants may be devised which are intended to contain and release suchcompounds or compositions. An example would be an implant made of apolymeric material adapted to release the compound over a period oftime.

An “effective amount” of a pharmaceutical composition as describedherein includes a therapeutically effective amount or a prophylacticallyeffective amount. A “therapeutically effective amount” refers to anamount effective, at dosages and for periods of time necessary, toachieve the desired therapeutic result, such as reduced tumor size,increased life span or increased life expectancy. A therapeuticallyeffective amount of a compound may vary according to factors such as thedisease state, age, sex, and weight of the subject, and the ability ofthe compound to elicit a desired response in the subject. Dosageregimens may be adjusted to provide the optimum therapeutic response. Atherapeutically effective amount is also one in which any toxic ordetrimental effects of the compound are outweighed by thetherapeutically beneficial effects. A “prophylactically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired prophylactic result, such assmaller tumors, increased life span, increased life expectancy orprevention of the progression of prostate cancer to anandrogen-independent form. Typically, a prophylactic dose is used insubjects prior to or at an earlier stage of disease, so that aprophylactically effective amount may be less than a therapeuticallyeffective amount.

It is to be noted that dosage values may vary with the severity of thecondition to be alleviated. For any particular subject, specific dosageregimens may be adjusted over time according to the individual need andthe professional judgment of the person administering or supervising theadministration of the compositions. Dosage ranges set forth herein areexemplary only and do not limit the dosage ranges that may be selectedby medical practitioners. The amount of active compound(s) in thecomposition may vary according to factors such as the disease state,age, sex, and weight of the subject. Dosage regimens may be adjusted toprovide the optimum therapeutic response. For example, a single bolusmay be administered, several divided doses may be administered over timeor the dose may be proportionally reduced or increased as indicated bythe exigencies of the therapeutic situation. It may be advantageous toformulate parenteral compositions in dosage unit form for ease ofadministration and uniformity of dosage.

In some embodiments, compounds and all different forms thereof asdescribed herein may be used, for example, and without limitation, incombination with other treatment methods for at least one indicationselected from the group consisting of: prostate cancer, breast cancer,ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovariancysts, polycystic ovary disease, precocious puberty and age-relatedmacular degeneration. For example, compounds and all their differentforms as described herein may be used as neoadjuvant (prior), adjunctive(during), and/or adjuvant (after) therapy with surgery, radiation(brachytherapy or external beam), or other therapies (eg. HIFU).

In general, compounds as described herein should be used without causingsubstantial toxicity. Toxicity of the compounds as described herein canbe determined using standard techniques, for example, by testing in cellcultures or experimental animals and determining the therapeutic index,i.e., the ratio between the LD50 (the dose lethal to 50% of thepopulation) and the LD100 (the dose lethal to 100% of the population).In some circumstances however, such as in severe disease conditions, itmay be appropriate to administer substantial excesses of thecompositions. Some compounds as described herein may be toxic at someconcentrations. Titration studies may be used to determine toxic andnon-toxic concentrations. Toxicity may be evaluated by examining aparticular compound's or composition's specificity across cell linesusing PC3 cells as a negative control that do not express AR. Animalstudies may be used to provide an indication if the compound has anyeffects on other tissues. Systemic therapy that targets the AR will notlikely cause major problems to other tissues since anti-androgens andandrogen insensitivity syndrome are not fatal.

Compounds as described herein may be administered to a subject. As usedherein, a “subject” may be a human, non-human primate, rat, mouse, cow,horse, pig, sheep, goat, dog, cat, etc. The subject may be suspected ofhaving or at risk for having a cancer, such as prostate cancer, breastcancer, ovarian cancer or endometrial cancer, or suspected of having orat risk for having acne, hirsutism, alopecia, benign prostatichyperplasia, ovarian cysts, polycystic ovary disease, precociouspuberty, or age-related macular degeneration. Diagnostic methods forvarious cancers, such as prostate cancer, breast cancer, ovarian canceror endometrial cancer, and diagnostic methods for acne, hirsutism,alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovarydisease, precocious puberty, or age-related macular degeneration and theclinical delineation of cancer, such as prostate cancer, breast cancer,ovarian cancer or endometrial cancer, diagnoses and the clinicaldelineation of acne, hirsutism, alopecia, benign prostatic hyperplasia,ovarian cysts, polycystic ovary disease, precocious puberty, orage-related macular degeneration are known to those of ordinary skill inthe art.

Definitions used include ligand-dependent activation of the androgenreceptor (AR) by androgens such as dihydrotestosterone (DHT) or thesynthetic androgen (R1881) used for research purposes.Ligand-independent activation of the AR refers to transactivation of theAR in the absence of androgen (ligand) by, for example, stimulation ofthe cAMP-dependent protein kinase (PKA) pathway with forskolin (FSK).

Some compounds and compositions as described herein may interfere with amechanism specific to ligand-dependent activation (e.g., accessibilityof the ligand binding domain (LBD) to androgen) or to ligand-independentactivation of the AR.

Various alternative embodiments and examples of the invention aredescribed herein. These embodiments and examples are illustrative andshould not be construed as limiting the scope of the invention.

Materials and Methods

In Silico Screening

Ten million commercially available compounds from the ZINC12.0structural libraries (Irwin, J. J. and Shoichet, B. K. ZINC—a freedatabase of commercially available compounds for virtual screening. JChem Inf Model 2005, 45, 177-182) were imported into a moleculardatabase using Molecular Operating Environment (MOE) version 2007.09(MOE, Chemical Computing Group, Inc., 2008, www.chemcomp.com). Thesestructures were energy minimized using an MMFF94x force field, exportedin SD format and rigidly docked into the BF3 site of the proteinstructures 4HLW with Glide software (Friesner, R. A. et al. Glide: a newapproach for rapid, accurate docking and scoring. 1. Method andassessment of docking accuracy. J Med Chem. 2004, 25, 739-49). About 2million molecules that had a GlideScore←5.0 were then re-docked into thesame BF3 binding cavity using the electronic high-throughput screening(eHiTS) docking module (Zsoldos, Z. et al. eHiTS: a new fast, exhaustiveflexible ligand docking system. J Mol Graph Model 2007, 26, 198-212).From this, 500,000 structures with eHiTS docking scores ←3.0 thresholdwere identified. They were scored by the LigX™ module of the MOE toaccount for the receptor/ligand flexibility. The pKi binding affinitywas scored after energy minimization to select the ligands that showedthe best binding characteristics defined mainly by the energy ofhydrogen bonds and hydrophobic interactions. The virtual hits werescored using Molecular Mechanics, the Generalized Born model and SolventAccessibility (MM-GB/SA) method with OPLS_2005 and GB/SA in MacroModel™to calculate the free energies of the optimal chemical poses (Maestro,Schrödinger, LLC, New York, N.Y., 2008. www.schrodinger.com). The rootmean square deviation (RMSD) was calculated between the Glide poses andthe eHiTS poses to evaluate the docking consistency and thus toestablish the most probable binding pose for a given ligand. Finally,very large and very small molecules were penalized based on a heavy atomcount.

With this information, a cumulative scoring of five different predictedparameters (RMSD, heavy atoms count, LigX, Macromodel, pKi) wasgenerated where each molecule receive a binary 1.0 score for every ‘top10% appearance’. The final cumulative vote (with the maximum possiblevalue of 5) was then used to rank the training set entries. Based on thecumulative score 5000 compounds were selected and subjected to visualinspection. After this final selection step 200 compounds were selectedout of which 150 chemical substances could be readily purchased insufficient purity and quantity.

General Synthesis and Characterization of Compounds

Exemplary Scheme 1: Synthesis of Compound 13163.

At 0° C., a solution of para-toluenesulfonic acid (13.4 g, 0.55 eq, 70.4mmol) in acetonitrile (150 mL) was added drop-wise over 1 h to asolution of indole (15 g, 1.0 eq, 128.0 mmol) in acetonitrile (500 mL).The mixture was kept for additional 6 h at 0° C. The subsequentprecipitate was filtered (at 0° C.) and washed with acetonitrile (threetimes). The precipitate was neutralized with saturated NaHCO₃ solutionand extracted with AcOEt (3×100 mL). The organic extracts were combined,washed with brine, dried over Na₂SO₄; filtered and concentrated underreduced pressure. Any purification was needed and the crude wastransformed in corresponding hydrochloride with HCl 2 M solution inether and the precipitate salt was filtered to afford 14.8 g of thewhite solid (54.7 mmol, 85%).

Analysis

M.p.=169-170° C.

t_(R) (HPLC)=3.01 min

MS (ESI+) m/z=235.12 [(M+H)⁺]

HRMS (ESI+): calculated for C₁₆H₁₅N₂, m/z=235.1230. found, 235.1237;calculated for C₁₆H₁₄N₂Na, m/z=257.1049. found, 257.1058.

¹H NMR (400 MHz, DMSO-d₆): δ (ppm)=1145 (s, 1H, H₁₂), 7.77 (d, J=8.0 Hz,1H, H₁₈), 7.68 (d, J=2.6 Hz, 1H, H₁₁), 7.58-7.50 (m, 1H, H₆), 7.45 (d,J=8.4 Hz, 1H, H₁₅), 7.43-7.38 (m, 4H, H_(1,2)), 7.35-7.33 (m, 1H, H₃)7.17 (ddd, J=8.2, 7.1, 1.1 Hz, 1H, H₁₆), 7.07 (ddd, J=8.0, 7.1, 1.0 Hz,1H, H₁₇), 5.58 (t, J=8.7 Hz, 1H, H₁₈), 3.67 (d, J=8.7 Hz, 2H, H₉).

¹³C NMR (101 MHz, DMSO-d₆): δ (ppm)=137.96 (C₄-arom.), 137.00(C₁₃-arom.), 135.72 (C₅-arom.), 128.74 (C₁H-arom.), 128.50 (C₂H-arom.),126.36 (C₁₄-arom.), 126.11 (C₆H-arom.), 125.72 (C₁₁H-arom.), 122.31(C₁₆H-arom.), 119.69 (C₁₇H-arom.), 119.48 (C₁₈H-arom.), 119.38(C₃H-arom.), 112.30 (C₁₅H-arom.), 110.24 (C₁₀-arom.), 56.55 (C₈H), 35.37(C₉H₂).

General Synthesis Methods

¹H and ¹³C NMR spectra (COSY, ¹H/¹³C 2D-correlations) were recorded withBruker Avance III™ 400 MHz. Processing of the spectra was performed withMestRec™ software and data are reported as follows: chemical shifts (δ)in parts per million, coupling constants (J) in hertz (Hz). Thehigh-resolution mass spectra were recorded in positive ion-mode with anESI ion source on an Agilent™ Time-of-Flight LC/MS mass spectrometer.HPLC analyses and purity of >95% were performed by analyticalreverse-phase HPLC with a Agilent™ instrument with variable detectorusing column Agilent Zorbax 4.6×5 mm, 5 um; flow: 2.0 mL·min⁻¹, H₂O(0.1% FA)/CH₃CN (0.1% FA), gradient 2→98% (6 min) and 98% (0.3 min).Melting points were determined with a Fischer-Jonhs.

Analytical Methods:

¹H and ¹³C NMR spectra (COSY, ¹H/¹³C 2D-correlations) were recorded withBruker Avance III™ 400 MHz. Processing of the spectra was performed withMestRec™ software and data are reported as follows: chemical shifts (δ)in parts per million, coupling constants (J) in hertz (Hz). Thehigh-resolution mass spectra were recorded in positive ion-mode with anESI ion source on an Agilent™ Time-of-Flight LC/MS mass spectrometer.HPLC analyses and purity of >95% were performed by analyticalreverse-phase HPLC with a Agilent™ instrument with variable detectorusing column Agilent Zorbax 4.6×5 mm, Sum; flow: 2.0 mL·min⁻¹, H₂O (0.1%FA)/CH₃CN (0.1% FA), gradient 2→98% (6 min) and 98% (0.3 min).

Dimethyl- & Cyclohexyl-Hydroindole Moiety

General Procedure 1

Phenylhydrazine (1.0 eq) aldehyde (isobutyraldehyde orcyclohexanecarboxaldehyde) (1.0 eq) were diluted in AcOH (0.1 M). Themixture was heated at 65° C. for 2 h (until complete conversion).Reaction mixture containing imine intermediate was allowed to reach r.t.and indole (1.0 eq) was added to the mixture which was stirredadditional 2 h at r.t. (until complete conversion). Acetic acid wasremoved under vacuo. Then, the residue was poured with H₂O andneutralized at pH 7 with sat. NaHCO₃ solution. The aqueous layer wasextracted with AcOEt (×3) and organic layers were combined, washed withbrine, dried over Na₂SO₄ and evaporated under reduced pressure. Then,crude was purified by automated combi-flash to afford the good compound.General Procedure 2Benzyloxy compound (1.0 eq) was dissolved in mixture of MeOH (0.05 M)and the system was purged with vacuum/N₂ (×3). Then, Pd/C (20% w/w) wasadded to the mixture and purged again with vacuum/H₂ and put under H₂atmosphere. The reaction was stirred overnight at r.t. under H₂atmosphere. The reaction mixture was filtered on a plug of Celite whichwas washed with MeOH. The filtrate was concentrated under reducedpressure and the residue was purified by combi-flash to afford the goodcompound.General Procedure 3Imine compound (1.0 eq) was dissolved in AcOH (0.1 M) and the system wasput under argon atmosphere. Then, NaBH₃CN (1.1 eq) was added quickly.Then, the reaction was stirred at r.t. After overnight, the reactionmixture was concentrated and the crude was quenched with H₂O. Aqueouslayer was neutralized with saturated NaHCO₃ solution until pH 7 andextracted with AcOEt (×2). The combined organic layers were washed withbrine, dried over Na₂SO₄ and rotary evaporated. The crude was purifiedby automated combi-flash to afford the good compound.General Procedure 4From ester compound (1.0 eq) was diluted in mixture of MeOH/Acetone(1:3, 0.1 M). The mixture was stirred and a solution of LiOH (2.0 eq) inH₂O (0.85 M) was added drop-wise over 5 min. Then, the mixture wasstirred overnight at r.t. The reaction mixture was diluted in a mixtureof Et₂O and H₂O and the aqueous phase was washed and then acidified withconcentrated HCl solution until pH 3. The aqueous layer was extractedwith Et₂O (×2). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive pure product.General Procedure 5A dried vessel was charged with LiAlH₄ (4.0 eq), enclosed with condenserand rubber cap and put under argon atmosphere. Then, carboxylic acid(1.0 eq) was dissolved in anhydrous THF (0.28 M) and was added in systemwhich was stirred 2 h at 70° C. The excess of LiAlH₄ was destroyed byadding AcOEt drop-wise (exothermic reaction) and then by adding H₂O.Aqueous saturated NH₄Cl solution was added and the whole was extractedwith AcOEt (×2). The combined organic layers were washed with H₂O andbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude was purified by automated combi-flash to afford thegood compound.General Procedure 6Phenylhydrazine (1.0 eq) and isobutyraldehyde (1.0 eq) were diluted inAcOH (0.1 M). The mixture was heated at 65° C. for 2 h (until completeconversion). Reaction mixture containing imine intermediate was allowedto reach r.t. Acetic acid was removed under vacuo. The residue waspoured with H₂O and neutralized at pH 7 with sat. NaHCO₃ solution. Theaqueous layer was extracted with AcOEt (×3) and organic layers werecombined, washed with brine, dried over Na₂SO₄ and evaporated underreduced pressure. Then, residue corresponding to imine intermediate wasdiluted in ACN (0.5 M). Azaindole (0.9 eq) and ZnCl₂ (0.9 eq) wereintroduced in microwave vessel. The mixture was stirred and heated bymicrowave 3 h at 120° C. The resulting crystals (after avernight atr.t.) was filtered and washed with 1 N aqueous NaOH solution (50 mL) andextracted with AcOEt (×2). The organic layers were combined, washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure toprovide pure compound.

Dimethyl-Hydroindole Moiety3-(3,3-dimethylindolin-2-yl)-5-methyl-1H-indole (Procedure 1)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.5 13 535 CA 2-36 F9-15 (yield =63%) IC₅₀ (PSA) = 1.87

t_(R) (HPLC) = 4.07 min MS (ESI+) m/z = 277.1719 [(M + H)⁺] HRMS (ESI+):calculated for C₁₉H₂₁N₂, m/z = 277.1699; found, 277.1708 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 10.83 (s, 1H, H₁₄, 7.33 (d, J = 0.6 Hz, 1H,H₂₀), 7.26 (d, J = 2.0 Hz, H₁₃), 7.25 (d, J = 8.0 Hz, 1H, H₁₇), 7.01 (d,J = 7.2 Hz 1H, H₆), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.88 (dd, J =8.3, 1.5 Hz, 1H, H₁₈), 6.60 (td, J = 7.6, 1.2 Hz, 1H, H₁), 6.59 (d, J =7.6 Hz, 1H, H₃), 5.82 (d, J = 2.4 Hz, 1H, H₇), 4.76 (d, J = 2.2 Hz, 1H,H₈), 2.33 (s, 3H, H₂₁), 1.39 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ¹³C NMR(101 MHz, DMSO-d₆): δ (ppm) = 150.99 (C₄-arom.), 138.68 (C₅-arom.),135.33 (C₁₅-arom.), 127.54 (C₁₉-arom.), 127.29 (C₂H-arom.), 127.01(C₁₆-arom.), 124.09 (C₁₃H-arom.), 122.80 (C₁₈H-arom.), 122.45(C₆H-arom.), 119.77 (C₂₀H- arom.), 117.53 (C₁H-arom.), 113.64(C₁₂-arom.), 111.60 (C₁₇H-arom.), 108.85 (C₃H- arom.), 68.17 (C₈H),45.20 (C₉), 27.15 (C₁₀H₃), 25.01 (C₁₁H₃), 21.87 (C₂₁H₃).

3-(3,3-dimethylindolin-2-yl)-5-methoxy-1H-indole (Procedure 1)

VPC Number LabBook Code IC₅₀ (eGFP) = 2.2 13 536 CA 2-38 F10-19 (yield =46%) IC₅₀ (PSA) = 2.52

t_(R) (HPLC) = 3.82 min MS (ESI+) m/z = 293.1668 [(M + H)⁺] HRMS (ESI+):calculated for C₁₉H₂₁N₂O, m/z = 293.1648; found, 293.1654 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 10.79 (s, 1H, H₁₄), 7.27 (d, J = 2.5 Hz, 1H,H₁₃), 7.24 (d, J = 8.8 Hz, 1H, H₁₇), 7.02 (br d, J = 7.2 Hz, 1H, H₆),6.97 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.88 (d, J = 2.4 Hz, 1H, H₂₀), 6.70(dd, J = 8.8, 2.4 Hz, 1H, H₁₈), 6.61 (td, J = 7.6, 1.2 Hz, 1H, H₁), 6.59(d, J = 7.6 Hz, 1H, H₃), 5.82 (d, J = 2.0 Hz, 1H, H₇), 4.73 (d, J = 1.9Hz, 1H, H₈), 3.62 (s, 3H, H₂₂), 1.38 (s, 3H, H₁₀), 0.78 (s, 3H, H₁₁).¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 153.22 (C₁₉-arom.), 151.10(C₄-arom.), 138.59 (C₅-arom.), 132.18 (C₁₅-arom.), 127.37 (C₂H-arom.),127.36 (C₁₆-arom.), 124.83 (C₁₃H-arom.), 122.32 (C₆H-arom.), 117.51(C₁H-arom.), 114.38 (C₁₂-arom.), 112.44 (C₁₇H-arom.), 111.21(C₁₈H-arom.), 108.72 (C₃H-arom.), 102.31 (C₂₀H- arom.), 68.27 (C₈H),55.63 (C₂₂H₃), 45.21 (C₉), 27.73 (C₁₀H₃), 24.58 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-5-amine-1H-indole (Procedure 1)

VPC Number LabBook Code IC₅₀ (eGFP) = 7.7 13 538 CA 2-47 F7-17 (yield =45%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 2.56 min MS (ESI+) m/z = 278.1668 [(M + H)⁺] HRMS (ESI+):calculated for C₁₈H₂₀N₃, m/z = 278.1652; found, 278.1657 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 10.53 (d, J = 1.6 Hz, 1H, H₁₄), 7.14 (d, J =2.4 Hz, 1H, H₁₃), 7.08 (d, J = 8.4 Hz, 1H, H₁₇), 7.00 (dd, J = 7.2, 0.7Hz, 1H, H₆), 6.95 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.86 (d, J = 2.0 Hz,1H, H₂₀), 6.60 (td, J = 7.6, 0.8 Hz, 1H, H₂), 6.57 (d, J = 7.6 Hz, 1H,H₃), 6.51 (dd, J = 8.5, 2.0 Hz, 1H, H₁₈), 5.78 (s, 1H, H₇, 4.86 (s, 2H,H₂₁), 4.69 (s, 1H, H₈), 1.39 (s, 3H, H₁₀, 0.75 (s, 3H, H₁₁). ¹³C NMR(101 MHz, DMSO-d₆): δ (ppm) = 150.97 (C₄-arom.), 138.81 (C₅-arom.),140.00 (C₁₉-arom.), 131.08 (C₁₅-arom.), 128.25 (C₁₆-arom.), 127.21(C₂H-arom.), 123.86 (C₁₃H-arom.), 122.47 (C₆H-arom.), 117.47(C₁H-arom.), 112.50 (C₁₂-arom.), 112.36 (C₁₈H-arom.), 111.97(C₁₇H-arom.), 108.86 (C₃H-arom.), 104.09 (C₂₀H- arom.), 68.29 (C₈H),45.21 (C₉), 27.00 (C₁₀H₃), 25.15 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-6-(benzyloxy)-1H-indole (Procedure 1)

VPC Number LabBook Code IC₅₀ (eGFP) = 11.4 13 544 CA 2-54 Precipitate(yield = 53%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 4.60 min MS (ESI+) m/z = 369.1981 [(M + H)⁺] HRMS (ESI+):calculated for C₂₅H₂₅N₂O, m/z = 369.1961; found, 369.1979 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 10.77 (s, 1H, H₁₄), 7.47 (d, J = 7.1 Hz, 2H,H_(24, 28)), 7.42-7.38 (m, 3H, H_(20, 25, 27)), 7.35-7.31 (m, 1H, H₂₆),7.18 (d, J = 2.1 Hz, 1H, H₁₃), 6.99 (d, J = 6.8 Hz, 1H, H₆), 6.98-6.94(m, 2H, H_(2, 17)), 6.69 (dd, J = 8.7, 2.3 Hz, 1H, H₁₉), 6.63-6.55 (m,2H, H_(1, 3)), 5.83 (d, J = 2.3 Hz, 1H, H₇), 5,11 (s, 2H, H₂₂), 4.73 (d,J = 2.2 Hz, 1H, H₈), 1.37 (s, 3H, H₁₀), 0.73 (s, 3H, H₁₁). ¹³C NMR (101MHz, DMSO-d₆): δ (ppm) = 154.69 (C₁₈-arom.), 150.96 (C₄- arom.), 138.64(C₅-arom.), 138.14 (C₂₃-arom.), 137.52 (C₁₅-arom.), 128.84 (C₂₅,₂₇H-arom.), 128.08 (C₂₆H-arom.), 127.96 (C_(24, 28)H-arom.),127.32(C₂H-arom.), 122.77 (C₁₃H-arom.), 122.41 (C₆H-arom.), 121.88(C₁₆-arom.), 120.79 (C₂₀H-arom.), 117.54 (C₁H-arom.), 114.22(C₁₂-arom.), 109.60 (C₁₉H-arom.), 108.83 (C₃H-arom.), 96.33(C₁₇H-arom.), 69.92 (C₂₂H₂), 68.20 (C₈H), 45.15 (C₉), 27.16 (C₁₀H₃),24.91 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-7-(benzyloxy)-1H-indole (Procedure 1)

VPC Number LabBook Code IC₅₀ (eGFP) = 3.7 13 543 CA 2-55 F7-10 (yield =61%) IC₅₀ (PSA) = 3.19

t_(R) (HPLC) = 4.67 min MS (ESI+) m/z = 369.1976 [(M + H)⁺] HRMS (ESI+):calculated for C₂₅H₂₅N₂O, m/z = 369.1961; found, 369.1957 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 11.10 (d, J = 1.6 Hz, 1H, H₁₄), 7.58 (d, J =7.8 Hz, 2H, H₂₄, ₂₈), 7.46-7.39 (m, 2H, H_(25, 27)), 7.38-7.31 (m, 1H,H₂₆), 7.22 (d, J = 2.4 Hz, 1H, H₁₃), 7.15 (d, J = 8.0 Hz, 1H, H₂₀), 7.00(d, J = 7.0 Hz, 1H, H₆), 6.96 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.85 (t, J= 7.8 Hz, 1H, H₁₉), 6.73 (d, J = 7.6 Hz, 1H, H₁₈), 6.62-6.56 (m, 2H,H_(1, 3)), 5.85 (d, J = 2.4 Hz, 1H, H₇), 5.26 (s, 2H, H₂₂), 4.77 (d, J =2.2 Hz, 1H, H₈), 1.38 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ¹³C NMR (101 MHz,DMSO-d₆): δ (ppm) = 150.95 (C₄-arom.), 145.54 (C₁₇-arom.), 138.61(C₅-arom.), 137.89 (C₂₃-arom.), 128.97 (C₁₆-arom.), 128.83(C_(25, 27)H-arom.), 128.17 (C₂₆H-arom.), 128.01 (C_(24, 28)H-arom.),127.32 (C₂H-arom.), 127.15 (C₁₅-arom.), 123.71 (C₁₃H-arom.), 122.43(C₆H-arom.), 119.23 (C₁₉H-arom.), 117.57 (C₁H-arom.), 114.81 (C₁₂-arom.), 113.19 (C₂₀H-arom.), 108.83 (C₃H-arom.), 103.08 (C₁₈H-arom.),69.56 (C₂₂H₂), 68.03 (C₈H), 45.20 (C₉), 27.19 (C₁₀H₃), 24.89 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-6-hydroxy-1H-indole (Procedure 2)

VPC Number LabBook Code IC₅₀ (eGFP) = 5.7 13 542 CA 2-61 F3-8 (yield =62%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.25 min MS (ESI+) m/z = 279.1485 [(M + H)⁺] HRMS (ESI+):calculated for C₁₈H₁₉N₂O, m/z = 279.1492; found, 279.1485 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 10.55 (s, 1H, H₁₄), 8.84 (s, 1H, H₂₁), 7.28 (d,J = 8.5 Hz, 1H, H₂₀), 7.08 (d, J = 2.0 Hz, 1H, H₁₃), 6.99 (d, J = 6.8Hz, 1H, H₆), 6.95 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.71 (d, J = 2.0 Hz,1H, H₁₇), 6.62-6.54 (m, 2H, H_(1, 3)), 6.47 (dd, J = 8.6, 2.2 Hz, 1H,H₁₉), 5.79 (d, J = 2.4 Hz, 1H, H₇), 4.70 (d, J = 2.1 Hz, 1H, H₈), 1.37(s, 3H, H₁₀), 0.73 (s, 3H, H₁₁). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =153.20 (C₁₈-arom.), 150.98 (C₄- arom.), 138.70 (C₅-arom.), 138.04(C₁₅-arom.), 127.28 (C₂H-arom.), 122.40 (C₆H-arom.), 121.88(C₁₃H-arom.), 120.84 (C₁₆-arom.), 120.50 (C₂₀H-arom.), 117.48(C₁H-arom.), 114.08 (C₁₂-arom.), 109-39 (C₁₉H-arom.), 108.78 (C₃H-arom.), 96.92 (C₁₇H-arom.), 68.27 (C₈H), 45.10 (C₉), 27.17 (C₁₀H₃),24.90 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-7-hydroxy-1H-indole (Procedure 2)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.5 13 541 CA 2-62 F6-11 (yield =37%) IC₅₀ (PSA) = 0.94

t_(R) (HPLC) = 3.51 min MS (ESI+) m/z = 279.1525 [(M + H)⁺] HRMS (ESI+):calculated for C₁₈H₁₉N₂O, m/z = 279.1492; found, 279.1496 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) =10.76 (s, 1H, H₁₄), 9.46 (s, 1H, H₂₁), 7.19 (d,J = 2.4 Hz, 1H, H₁₃), 7.02-6.98 (m, 2H, H_(6, 20)), 6.96 (td, J = 7.6,1.3 Hz, 1H, H₂), 6.73 (t, J = 7.7 Hz, 1H, H₁₉), 6.62-6.55 (m, 2H,H_(1, 3)), 6.48 (dd, J = 7.5, 0.6 Hz, 1H, H₁₈), 5.82 (d, J = 2.4 Hz, 1H,H₇), 4.75 (d, J = 2.2 Hz, 1H, H₈), 1.38 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁).¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.98 (C₄-arom.), 143-94 (C₁₇-arom.), 138.67 (C₅-arom.), 129.24 (C₁₆-arom.), 127.29 (C₂H-arom.),126.97 (C₁₅H-arom.), 123.40 (C₁₃H-arom.), 122.41 (C₆H-arom.), 119.42(C₁₉H-arom.), 117.52 (C₁H-arom.), 114.60 (C₁₂-arom.), 111.24(C₂₀H-arom.), 108.80 (C₃H- arom.), 105.55 (C₁₈H-arom.), 68.08 (C₈H,45.16 (C₉), 27.21 (C₁₀H₃), 24.88 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-7-methyl-1H-indole (Procedure 1)

VPC Number LabBook Code IC₅₀ (eGFP) = No Data 13 546 CA 2-67 F4-10(yield = 62%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 4.16 min MS (ESI+) m/z = 277.1705 [(M + H)⁺] HRMS (ESI+):calculated for C₁₉H₂₁N₂, m/z = 277.1699; found, 277.1707 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 10.94 (s, 1H, H₁₄), 7.39-7.35 (m, 1H, H₂₀),7.31 (d, J = 2.4 Hz, 1H, H₁₃), 7.01 (d, J = 7.2 Hz, 1H, H₆), 6.97 (td, J= 7.6, 1.3 Hz, 1H, H₂), 6.87-6.83 (m, 2H, H_(18, 19)), 6.61 (td, J =7.2, 0.8 Hz, 1H, H₁), 6.58 (d, J = 7.6 Hz, 1H, H₃), 5.84 (d, J = 2.4 Hz,1H, H₇), 4.80 (d, J = 2.2 Hz, 1H, H₈), 2.46 (s, 3H, H₂₁), 1.39 (s, 3H,H₁₀), 0.74 (s, 3H, H₁₁). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.97(C₄-arom.), 138.68 (C₅- arom.), 136.42 (C₁₅-arom.), 127.32 (C₂H-arom.),126.97 (C₁₆-arom.), 123.73 (C₁₃H-arom.), 122.42 (C₆H-arom.), 121.72(C₁₉H-arom.), 120.90 (C₁₇-arom.), 118.96 (C₁₈H-arom.), 117.73(C₂₀H-arom.), 117.57 (C₁H-arom.), 114.63 (C₁₂- arom.), 108.85(C₃H-arom.), 68.11 (C₈H), 45.17 (C₉), 27.16 (C₁₀H₃), 24.95 (C₁₁H₃),17.27 (C₂₁H₃).

3-(3,3-dimethylindolin-2-yl)-7-fluoro-1H-indole (Procedure 1)

VPC Number LabBook Code IC₅₀ (eGFP) = No Data 13 555 CA 2-90 F4-7 (yield= 62%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 4.12 min MS (ESI+) m/z = 281.1456 [(M + H)⁺] HRMS (ESI+):calculated for C₁₈H₁₈FN₂, m/z = 281.1449; found, 281.1454 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 11.49 (s, 1H, H₁₄), 7.41-7.34 (m, 2H,H_(13, 20)), 7.01 (d, J = 7.2 Hz, 1H, H₆), 6.97 (td, J = 7.6, 1.3 Hz,1H, H₂), 6.94- 6.86 (m, 2H, H_(18, 19)), 6.65-6.57 (m, 2H, H_(1, 3)),5.91 (d, J = 2.5 Hz, 1H, H₇), 4.79 (d, J = 2.2 Hz, 1H, H₈), 1.38 (s, 3H,H₁₀), 0.74 (s, 3H, H₁₁). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.85(C₄-arom.), 148.48 (C₁₇- arom.), 138.51 (C₅-arom.), 131.28 (d, J = 5.9Hz, C₁₆-arom.), 127.39 (C₂H- arom.), 125.19 (d, J = 0.6 Hz, C₁₃H-arom.),124.70 (d, J = 13.1 Hz, C₁₅-arom.), 122.45 (C₆H-arom.), 119.05 (d, J =6.3 Hz, C₁₉H-arom.), 117.70 (C₁H-arom.), 116.45 (d, J = 3.2 Hz,C₂₀H-arom.), 115.49 (d, J = 1.9 Hz, C₁₂-arom.), 108.91 (C₃H-arom.),106.02 (d, J = 15.9 Hz, C₁₈H-arom.), 67.86 (C₈H, 45.25 (C₉), 27.12(C₁₀H₃), 24.90 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 3)

VPC Number LabBook Code IC₅₀ (eGFP) = 2.1 13 556 CA 2-100 F3-7 (yield =76%) IC₅₀ (PSA) = 2.18

t_(R) (HPLC) = 3.52 min MS (ESI+) m/z = 264.1501 [(M + H)⁺] HRMS (ESI+):calculated for C₁₇H₁₈N₃, m/z = 264.1495; found, 264.1500 ¹H NMR (600MHz, DMSO-d₆): δ (ppm) = 11.51 (s, 1H, H₁₄), 8.18 (dd, J = 4.6, 1.5 Hz,1H, H₂₀), 7.86 (dd, J = 7.9, 1.1 Hz, 1H, H₁₈), 7.44 (d, J = 2.4 Hz, 1HH₁₃), 7.02 (d, J = 7.2 Hz, 1H, H₆), 7.00-6.96 (m, 2H, H_(2, 19)), 6.63(td, J = 7.4, 0.9 Hz, 1H, H₁), 6.60 (d, J = 7.7 Hz, 1H, H₃), 5.92 (d, J= 2.3 Hz, 1H, H₇), 4.74 (d, J = 2.0 Hz, 1H, H₈), 1.38 (s, 3H, H₁₀), 0.74(s, 3H, H₁₁). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 150.38 (C₄-arom.),148.74 (C₁₅- arom.), 142.28 (C₂₀H-arom.), 137.95 (C₅-arom.), 127-99(C₁₈H-arom.), 126.96 (C₂H-arom.), 123.93 (C₁₃H-arom.), 121.97(C₆H-arom.), 118.98 (C₁₆-arom.), 117.26 (C₁H-arom.), 114.92(C₁₉H-arom.), 112.80 (C₁₂-arom.), 108.47 (C₃H- arom.), 67.77 (C₈H),44.77 (C₉), 26.62 (C₁₀H₃), 24.34 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-1H-indole-7-carboxylic acid (Procedure 4)

VPC Number LabBook Code IC₅₀ (eGFP) = No Data 13 557 CA 2-104 Ap Tmt(yield = 82%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.74 min MS (ESI+) m/z = 307.1442 [(M + H)⁺] HRMS (ESI+):calculated for C₁₉H₁₉N₂O₂, m/z = 307.1441; found, 304.1442 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 13.01 (br s, 1H, H₂₂), 10.98 (s, 1H, H₁₄), 7.87(d, J = 7.8 Hz, 1H, H₂₀), 7.74 (d, J = 6.8 Hz, 1H, H₁₈), 7.35 (d, J =2.3 Hz, 1H, H₁₃), 7.07 (t, J = 7.7 Hz, 1H, H₁₉), 7.02 (d, J = 7.2 Hz,1H, H₆), 6.98 (td, J = 7.6, 1.1 Hz, 1H, H₂), 6.65-6.58 (m, 2H,H_(1, 3)), 5.93 (br s, 1H, H₇), 4.83 (s, 1H, H₈), 1.39 (s, 3H, H₁₀),0.73 (s, 3H, H₁₁). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 168.45 (C₂₁O),150.89 (C₄- arom.), 138.46 (C₅-arom.), 135.63 (C₁₅-arom.), 128.93(C₁₆-arom.), 127.41 (C₂H-arom.), 125.68 (C₂₀H-arom.), 125.66(C₁₃H-arom.), 124.20 (C₁₈H- arom.), 122.48 (C₆H-arom.), 118.42(C₁₉H-arom.), 117.69 (C₁H-arom.), 114.65 (C₁₂-arom.), 113.89(C₁₇-arom.), 108.90 (C₃H-arom.), 67.76 (C₈H) 45.25 (C₉), 27.08 (C₁₀H₃),24.91 (C₁₁H₃).

3-(3,3-dimethylindolin-9-yl)-1H-indole-7-yl)methanol (Procedure 5)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.6 13 558 CA 2-105 F6-11 (yield =81%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.45 min MS (ESI+) m/z = 293.1651 [(M +H)⁺] HRMS (ESI+):calculated for C₁₉H₂₁N₂O, m/z = 293.1648; found, 293.1651 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 10.82 (s, 1H, H₁₄), 7.45 (d, J = 7.8 Hz, 1H,H₂₀), 7.29 (d, J = 2.4 Hz, 1H, H₁₃), 7.05 (d, J = 6.8 Hz, 1H, H₁₈), 7.01(d, J = 7.2 Hz, 1H, H₆), 6.97 (td, J = 7.6, 1.3 Hz, 1H, H₂), 6.92 (dd, J= 7.8, 6.8 Hz, 1H), 6.61 (m, 2H, H_(1, 3)), 5.84 (d, J = 2.4 Hz, 1H,H₇), 5.14 (t, J = 5.7 Hz, 1H, H₁₈), 4.81 (d, J = 2.1 Hz, 1H, H₈), 4.78(d, J = 5.7 Hz, 2H, H₂₁), 1.39 (s, 3H, H₁₀), 0.74 (s, 3H, H₁₁). ¹³C NMR(101 MHz, DMSO-d₆): δ (ppm) = 150.97 (C₄-arom.), 138.66 (C₅H- arom.),134.66 (C₁₅-arom.), 127.36 (C₂H-arom.), 127.32 (C₁₆-arom.), 125.92(C₁₇-arom.), 123.87 (C₁₃H-arom.), 122.43 (C₆H-arom.), 119.41(C₁₈H-arom.), 118.92 (C₂₀H-arom.), 118.62 (C₁₉H-arom.), 117.57(C₁H-arom.), 114.36 (C₁₂- arom.), 108.85 (C₃H-arom.), 68.06 (C₈H), 60.82(C₂₁H₂), 45.19 (C₉), 27.15 (C₁₀H₃), 24.94 (C₁₁H₃).

3-(3,3-dimethylindolin-2-yl)-1H-pyrrolo[2,3-c]pyridine (Procedure 6)

VPC Number LabBook Code IC₅₀ (eGFP) = 10.7 13 561 CA 2-121 Ap Tmt (yield= 35%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.07 min MS (ESI+) m/z = 264.1497 [(M + H)⁺] HRMS (ESI+):calculated for C₁₇H₁₈N₃, m/z = 264.1495; found, 264.1498 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 11.52 (s, 1H, H₉), 8.73 (s, 1H, H₃), 8.03 (s,1H, H₅), 7.59 (d, J = 1.7 Hz, 1H, H₈), 7.49 (d, J = 4.3 Hz, 1H, H₆),7.04-6.95 (m, 2H, H_(11, 15)), 6.66-6.58 (m, 2H, H_(10, 12)), 5.94 (d, J= 1.9 Hz, 1H, H₁₆), 4.78 (d, J = 2.3 Hz, 1H, H₁₇), 1.38 (s, 3H, H₁₉),0.72 (s, 3H, H₂₀). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 150.34(C₁₃-arom.), 137-94 (C₁₄- arom.), 137.08 (C₅H-arom.), 134.44(C₃H-arom.), 133.68 (C₂-arom.), 130.91 (C₁-arom.), 127.79 (C₈H-arom.),126.96 (C₁₁H-arom.), 121.98 (C₁₅H-arom.), 117.32 (C₁₀H-arom.), 114.54(C₆H-arom.), 113.67 (C₇-arom.), 108.51 (C₁₂H- arom.), 67.25 (C₁₇H),44.83 (C₁₈), 26.51 (C₁₉H₃), 24.33 (C₂₀H₃).

3-(3,3-dimethylindolin-2-yl)-1H-pyrrolo[3,2-b]pyridine (Procedure 6)

VPC Number LabBook Code IC₅₀ (eGFP) = 2.3 13560 CA 2-123 Ap Tmt (yield =72%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 3.05 min MS (ESI+) m/z = 264.1502 [(M + H)⁺] HRMS (ESI+):calculated for C₁₇H₁₈N₃, m/z = 264.1495; found, 264.1502 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 11.16 (s, 1H, H₉), 8.32 (dd, J = 4.6, 1.5 Hz,1H, H₅), 7.75 (dd, J = 8.2, 1.5 Hz, 1H, H₃), 7.58 (d, J = 2.1 Hz, 1H,H₈), 7.09 (dd, J = 8.2, 4.6 Hz, 1H, H₄), 6.99 (d, J = 7.2 Hz, 1H, H₁₅),6.96 (td, J = 7.6, 1.3 Hz, 1H, H₁₁), 6.63-6.57 (m, 2H, H_(10, 12)), 5.86(d, J = 2.7 Hz, 1H, H₁₆), 5.06 (dd, J = 2.8, 0.6 Hz, 1H, H₁₇), 1.51 (s,3H, H₁₉), 0.72 (s, 3H, H₂₀). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =150.85 (C₁₃H-arom.), 145.29 (C₁- arom.), 142.28 (C₅H-arom.), 139.08(C₁₄-arom.), 129.27 (C₂-arom.), 127.40 (C₈H-arom.), 127.23 (C₁₁H-arom.),122.51 (C₁₅H-arom.), 118.77 (C₃H-arom.), 117.72 (C₁₀H-arom.), 116.55(C₄H-arom.), 115.09 (C₇-arom.), 108.96 (C₁₂H- arom.), 65.98 (C₁₇H),45.02 (C₁₈), 27.20 (C₁₉H₃), 25.21 (C₂₀H₃).

Cyclohexyl-Hydroindole Moiety3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-1H-indole (Procedure 1)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.8 13 534 CA 2-8 F18-23 (yield =47%) IC₅₀ (PSA) = 1.25

t_(R) (HPLC) = 4.39 min MS (ESI+) m/z = 303.1775 [(M + H)⁺] HRMS (ESI+):calculated for C₂₁H₂₃N₂, m/z = 303.1856; found, 303.1852 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 10.92 (s, 1H, H₁₂), 7.32 (d, J = 8.0 Hz, 1H,H₁₈), 7.27 (d, J = 2.4 Hz, 1H, H₁₁), 7.17 (d, J = 7.1 Hz, 1H, H₆),7.02-6.96 (m, 3H, H_(2, 15, 17)), 6.78 (td, J = 7.6, 0.8 Hz, 1H, H₁₆),6.61 (td, J = 7.4, 1.0 Hz, 1H, H₁), 6.53 (d, J = 7.4 Hz, 1H, H₃), 5.71(s, 1H, H₇), 4.83 (s, 1H, H₈), 1.82 -1.14 (m, 2H,H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 151.59(C₄-arom.), 137.65 (C₅-arom.), 137.07 (C₁₃-arom.), 127.58 (C₂H-arom.),126.78 (C₁₄-arom.), 124.83 (C₁₁H-arom.), 123.58 (C₆H-arom.), 121.08(C₁₇H-arom.), 120.68 (C₁₅H-arom.), 118.75 (C₁₆H- arom.), 117.00(C₁H-arom.), 115.58 (C₁₀-arom.), 111.86 (C₁₈H-arom.), 108.32(C₃H-arom.), 65.96 (C₈H), 48.29 (C₉), 37.43 (C₁₉H₂), 31.94 (C₂₃H₂),25.99 (C₂₁H₂), 22.96 (C₂₀H₂), 22.81 (C₂₂H₂).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-5-methyl-1H-indole (Procedure1)

VPC Number LabBook Code IC₅₀ (eGFP) = 3.2 13 548 CA 2-72 F12-18 (yield =69%) IC₅₀ (PSA) = 4.24

  (Beige Solid) t_(R) (HPLC) = 4.57 min MS (ESI+) m/z = 317.1950 [(M +H)⁺] HRMS (ESI+): calculated for C₂₂H₂₅N₂, m/z = 317.2012; found,317.2008 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.78 (d, J = 1.4 Hz, 1H,H₉), 7.22- 7.19 (m, 2H, , H_(3, 8)), 7.17 (d, J = 7.6 Hz, 1H, H₁₅), 7.00(td, J = 7.6, 1.2 Hz, 1H, H₁₁), 6.82 (dd, J = 8.3, 1.5 Hz, 1H, H₄), 6.75(br s, 1H, H₆), 6.62 (td, J = 7.4, 1.0 Hz, 1H, H₁₀), 6.53 (d, J = 7.6Hz, 1H, H₁₂), 5.65 (s, 1H, H₁₆), 4.78 (s, 1H, H₁₇), 2.18 (s, 3H, H₂₄),1.80-1.16 (H, 10H, H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆):δ (ppm) = 151.69 (C₁₃-arom.), 137.72 (C₁₄-arom.), 135.43 (C₂-arom.),127.45 (C₁₁H-arom.), 127.03 (C₅-arom.), 126.85 (C₁-arom.), 124.83(C₈H-arom.), 123.64 (C₁₅H-arom.), 122.62 (C₄H-arom.), 120.51 (C₆H-arom.), 116.95 (C₁₀H-arom.), 114.98 (C₇-arom.),111.51 (C₃H-arom.),108.44 (C₁₂H- arom.), 66.18 (C₁₇H), 48.25 (C₁₈), 37.22 (C₁₉H₂), 31.96(C₂₃H₂), 26.00 (C₂₁H₂), 23.01 (C₂₀H₂), 22.75 (C₂₂H₂), 21.88 (C₂₄H₃).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-7-methyl-1H-indole (Procedure1)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.7 13 549 CA 2-73 F9-15 (yield =72%) IC₅₀ (PSA) = 2.57

  (Beige Solid) t_(R) (HPLC) = 4.58 min MS (ESI+) m/z = 317.1932 [(M +H)⁺] HRMS (ESI+): calculated for C₂₂H₂₅N₂, m/z = 317.2012; found,317.2022 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.88 (s, 1H, H₉), 7.25(d, J = 2.5 Hz, 1H, H₈), 7.16 (d, J = 7.0 Hz, 1H, H₁₅), 6.98 (td, J =7.6, 1.2 Hz, 1H, H₁₁), 6.85 (d, J = 7.9 Hz, 1H, H₆), 6.8o (d, J = 7.0Hz, 1H, H₄), 6.70 (t, J = 7.6 Hz, 1H, H₅), 6.60 (td, J = 7.4, 1.0 Hz,1H, H₁₀), 6.53 (dd, J = 7.6, 0.4 Hz, 1H, H₁₂), 5.67 (s, 1H, H₁₆), 4.82(s, 1H, H₁₇), 2.43 (s, 3H, H₂₄), 1.83-1.17 (m, 10H,H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 151.60(C₁₃-arom.), 137.67 (C₁₄- arom.), 136.53 (C₂-arom.), 127.56(C₁₁H-arom.), 126.48 (C₁-arom.), 124.52 (C₈H- arom.), 123.60(C₁₅H-arom.), 121.61 (C₄H-arom.), 120.80 (C₃-arom.), 118.95 (C₅H-arom.),118.30 (C₆H-arom.), 116.98 (C₁₀H-arom.), 116.02 (C₇-arom.), 108.33(C₁₂H-arom.), 66.00 (C₁₇H), 48.28 (C₁₈), 37.44 (C₁₉H₂), 31.95 (C₂₃H₂),26.00 (C₂₁H₂), 22.97 (C₂₀H₂), 22.80 (C₂₂H₂), 17.25 (C₂₄H₃).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-6-(benzyloxy)-1H-indole(Procedure 1)

VPC Number LabBook Code IC₅₀ (eGFP) = 11.8 13 550 CA 2-76 F13-24 (yield= 55%) IC₅₀ (PSA) = No Data

  (Beige Solid) t_(R) (HPLC) = 5.07 min MS (ESI+) m/z = 409.2254 [(M +H)⁺] HRMS (ESI+): calculated for C₂₈H₂₉N₂O, m/z = 409.2274; found,409.2278 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.72 (d, J = 1.7 Hz, 1H,H₁₂), 7.46- 7.42 (m, 2H, H_(22, 26)), 7.41-7.36 (m, 2H, H_(23, 25)),7.34-7.30 (m, 1H, , H₂₄), 7.17-7.12 (m, 2H, , H_(6, 11)), 6.98 (td, J =7.6, 1.2 Hz, 1H, H₂), 6.89 (d, J = 2.2 Hz, 1H, H₁₅), 6.82 (br d, J = 8.7Hz, 1H, H₁₈), 6.60 (td, J = 7.4, 1.0 Hz, 1H, H₁), 6.54-6.50 (m, 2H, ,H₃₋₁₇), 5.67 (s, 1H, H₇), 5.07 (s, 2H, H₂₀), 4.76 (s, 1H, H₈), 1.80-1.15(m, 10H, H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =154.56 (C₁₆-arom.), 151.55 (C₄- arom.), 138.16 (C₂₁-arom.), 137.71(C₅-arom.), 137.65 (C₁₃-arom.), 128.82 (C₂₃, ₂₅H-arom.), 128.04(C₂₄H-arom.), 127.88 (C_(22, 26)H-arom.), 127.58 (C₂H- arom.), 123.67(C₆H-arom.), 123.54 (C₁₁H-arom.), 121.34 (C₁₄-arom.), 121.31(C₁₈H-arom.), 116.98 (C₁H-arom.), 115.58 (C₁₀-arom.), 109.47(G₁₇H-arom.), 108.32 (C₃H-arom.), 96.43 (C₁₅H-arom.), 69.87 (C₂₀H₂),66.04 (C₈H), 48.22 (C₉), 37.40 (C₁₉H₂), 31.91 (C₂₃H₂), 25.99 (C₂₁H₂),22.95 (C₂₀H₂), 22.83 (C₂₂H₂).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-6-hydroxy-1H-indole (Procedure2)

VPC Number LabBook Code IC₅₀ (eGFP) = 15.5 13 551 CA 2-83 F2-7 (yield =38%) IC₅₀ (PSA) = No Data

  (Beige Solid) t_(R) (HPLC) = 3.57 min MS (ESI+) m/z = 319.1824 [(M +H)⁺] HRMS (ESI+): calculated for C₂₁H₂₃N₂O, m/z = 319.1805; found,319.1802 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.51 (d, J = 1.5 Hz, 1H,H₁₂), 8.79 (s, 1H, H₂₄), 7.15 (d, J = 7.0 Hz, 1H, H₆), 7.04 (d, J = 2.3Hz, 1H, H₁₁), 6.97 (td, J = 7.6, 1.2 Hz, 1H, H₂), 6.72 (d, J = 8.5 Hz,1H, H₁₈), 6.67 (d, J = 2.0 Hz, 1H, H₁₅), 6.59 (td, J = 7.4, 1.0 Hz, 1H,H₁), 6.51 (d, J = 7.7 Hz, 1H, H₃), 6.30 (dd, J = 8.6, 2.2 Hz, 1H, H₁₇),5.64 (s, 1H, H₇), 4.73 (s, 1H, H₈), 1.81-1.16 (m, 10H,H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 153.10(C₁₆-arom.), 151.57 (C₄- arom.), 138.21 (C₁₃-arom.), 137.70 (C₅-arom.),127.52 (C₂H-arom.), 123.55 (C₆H-arom.), 122.74 (C₁₁H-arom.), 121.06(C₁₈H-arom.), 120.26 (C₁₄-arom.), 116.91 (C₁H-arom.), 115.43(C₁₀-arom.), 109.35 (C₁₇H-arom.), 108.29 (C₃H- arom.), 96.85(C₁₅H-arom.), 66.16 (C₈H), 48.18 (C₉), 37.38 (C₁₉H₂), 31.91 (C₂₃H₂),26.01 (C₂₁H₂), 22.97 (C₂₀H₂), 22.83 (C₂₂H₂).

3-spiro[cyclohexane-1,3′-indolin]-2′-yl)-7-hydroxy-1H-indole (Procedure2)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.1 13 552 CA 2-84 Precipitate(yield = 28%) IC₅₀ (PSA) = 1.14

  (Brown Solid) t_(R) (HPLC) = 3.81 min MS (ESI+) m/z = 319.1728 [(M +H)⁺] HRMS (ESI+): calculated for C₂₁H₂₃N₂O, m/z = 319.1805; found,319.1814 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 10.72 (d, J = 1.8 Hz, 1H,H₁₂), 9.42 (s, 1H, H₂₄), 7.14 (d, J = 7.1 Hz, 1H, H₆), 7.12 (d, J = 2.5Hz, 1H, H₁₁), 6.97 (td, J = 7.6, 1.2 Hz, 1H, H₂), 6.59 (m, 2H,H_(1, 17)), 6.52 (m, 2H, H_(3, 18)), 6.42 (dd, J = 7.4, 0.8 Hz, 1H,H₁₆), 5.65 (s, 1H, H₇), 4.79 (s, 1H, H₈), 1.82-1.16 (m, 10H,H_(19, 20, 21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 151.60(C₄-arom.), 143.87 (C₁₅- arom.), 137.66 (C₅-arom.), 128.78 (C₁₄-arom.),127.50 (C₂H-arom.), 127.06 (C₁₃-arom.), 124.10 (C₁₁H-arom.), 123.60(C₆H-arom.), 119.38 (C₁₇H-arom.), 116.93 (C₁H-arom.), 115.94(C₁₀-arom.), 111.78 (C₁₈H-arom.), 108.29 (C₃H- arom.), 105.41(C₁₆H-arom.), 65.88 (C₈H, 48.33 (C₉), 37.45 (C₁₉H₂), 31.93 (C₂₃H₂),26.00 (C₂₁H₂), 22.98 (C₂₀H₂), 22.79 (C₂₂H₂).Unexpected Compounds—General Procedure 7Phenylhydrazine (1.0 eq) aldehyde (isobutyraldehyde orcyclohexanecarboxaldehyde) (1.0 eq) were diluted in AcOH (0.1 M). Themixture was heated at 65° C. for 2 h (until complete conversion). Then,7-azaindole or 1,5,6,7-Tetrahydro-4H-indol-4-one (1.0 eq) was added andthe reaction mixture was stirred additional 24 h at 100° C. (untilcomplete conversion). Acetic acid was removed under vacuo. Then, theresidue was poured with H₂O and neutralized at pH 7 with sat. NaHCO₃solution. The aqueous layer was extracted with AcOEt (×3) and organiclayers were combined, washed with brine, dried over Na₂SO₄ andevaporated under reduced pressure. Then, crude was purified by automatedcombi-flash to afford the good compound.

3-(3,3-dimethyl-3H-indol-2-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 7)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.7 13 537 CA 2-39 F9-15 (yield =25%) IC₅₀ (PSA) = 0.81

  (Yellow Solid) t_(R) (HPLC) = 3.17 min MS (ESI+) m/z = 262.1345 [(M +H)⁺] HRMS (ESI+): calculated for C₁₇K₆N₃, m/z = 262.1339; found,262.1345 ¹H NMR (400 MHz, DMSO-d₆); δ (ppm) = 12.40 (s, 1H, H₁₄), 8.94(dd, J = 7.9, 1.7 Hz, 1H, H₁₈), 8.40 (s, 1H, H₁₃), 8.35 (dd, J = 4.6,1.6 Hz, 1H, H₂₀), 7.56 (d, J = 7.5 Hz, 1H, H₃), 7.49 (d, J = 6.8 Hz, 1H,H₆), 7.32 (td, J = 7.6, 1.2 Hz, 1H, H₂), 7.28 (dd, J = 7.9, 4.7 Hz, 1H,H₁₉), 7.20 (td, J = 7.4, 1.0 Hz, 1H, H₁), 1.54 (s, 6H, H_(10, 11)). ¹³CNMR (101 MHz, DMSO-d₆): δ (ppm) = 180.97 (C₈), 154.77 (C₄-arom.), 149.39(C₁₅-arom.), 146.90 (C₅-arom.), 144.50 (C₂₀H-arom.), 131.69(C₁₈H-arom.), 130.45 (C₁₃H-arom.), 127.92 (C₂H-arom.), 124.80(C₁H-arom.), 121.61 (C₆H-arom.), 119.71 (C₃H-arom.), 119.05 (C₁₆-arom.),117.73 (C₁₉H-arom.), 108.26 (C₁₂-arom.), 53.39 (C₉), 25.82 (C_(10, 11)).

Tetrahydro-3-(3,3-dimethyl-3H-indol-2-yl)-1H-indol-4-one (Procedure 7)

VPC Number LabBook Code IC₅₀ (eGFP) = No Data 13 539 CA 2-48 F19-22(yield = 9%) IC₅₀ (PSA) = No Data

  (Yellow Solid) t_(R) (HPLC) = 3.54 min MS (ESI+) m/z = 279.1498 [(M +H)⁺] HRMS (ESI+): calculated for C₁₈H₁₉N₂O, m/z = 279.1492; found,279.1498 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.27 (s, 1H, H₁₄),7.54-7.48 (m, 2H, H_(3, 6)), 7.33 (td, J = 7.6, 1.3 Hz, 1H, H₂), 7.22(td, J = 7.4, 1.0 Hz, 1H, H₁), 7.05 (d, J = 1.8 Hz, 1H, H₁₃), 2.85 (t, J= 6.1 Hz, 2H, H₁₇), 2.39 (t, J = 6.4 Hz, 2H, H₁₇), 2.09- 2.02 (m, 2H,H₁₈), 1.46 (s, 6H, H_(10, 11)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =193.35 (C₂₀O), 176.21 (C₈), 153.76 (C₄- arom.), 148.19 (C₁₅-arom.),147.25 (C₅-arom.), 128.13 (C₂H-arom.), 126.38 (C₁₂- arom.), 125.40(C₁H-arom.), 121.96 (C₆H-arom.), 121.76 (C₁₆-arom.), 119.76 (C₃H-arom.), 109.82 (C₁₃H-arom.), 52.57 (C₉), 38.25 (C₁₉H₂), 25.49(C_(10, 11)H₃), 23.71 (C₁₈H₂), 22.70 (C₁₇H₂).

3-(spiro[cyclohexane-1,3′-indolin]-2′-yl)-1H-pyrrolo[2,3-b]pyridine(Procedure 7)

VPC Number LabBook Code IC₅₀ (eGFP) = 6.6 13 559 CA 2-110 F18-27 (yield= 23%) IC₅₀ (PSA) = No Data

  (Brown Solid) t_(R) (HPLC) = 3.70 min MS (ESI+) m/z = 302.1654 [(M +H)⁺] HRMS (ESI+): calculated for C₂₀H₂₀N₃, m/z = 302.1652; found,302.1654 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.39 (s, 1H, H₁₇), 9.00(dd, J = 7.9, 1.7 Hz, 1H, H₂₁), 8.45 (d, J = 2.0 Hz, 1H, H₁₆), 8.35 (dd,J = 4.6, 1.6 Hz, 1H, H₂₃), 7.87 (d, J = 7.3 Hz, 1H, H₆), 7.62 (dd, J =7.6, 0.6 Hz, 1H, H₃), 7.38 (td, J = 7.6, 1.0 Hz, 1H, H₂), 7.27 (dd, J =7.9, 4.7 Hz, 1H, H₂₂), 7.17 (td, J = 7.5, 1.1 Hz, 1H, H₁), 2.34-2.25 (m,2H, H₁₀), 2.07-1.77 (m, 6H, H_(11, 12, 13)), 1.32-1.26 (m, 2H, H₁₄). ¹³CNMR (101 MHz, DMSO-d₆): δ (ppm) = 180.61 (C₈), 155.41 (C₄-arom.), 149.19(C₁₈-arom.), 145.63 (C₅-arom.), 144.45 (C₂₃H-arom.), 132.08(C₂₁H-arom.), 130.23 (C₁₆H-arom.), 127.95 (C₂H-arom.), 124.74(C₆H-arom.), 123.93 (C₁H-arom.), 120.36 (C₃H-arom.), 119.45 (C₁₉-arom.),117.71 (C₂₂H-arom.), 107.92 (C₁₅-arom.), 57.86 (C₉), 33.53(C_(10, 14)H₂), 24.81 (C₁₂H₂), 21.89 (C_(11, 13)H₂).Quinoline Moiety—General Procedure 9In microwave vessel, quinoline (2.0 eq) and indole ((1.0 eq)) were mixedtogether and the system was sealed and placed under nitrogen, after apurge with vacuum/N₂ (3 times). Then, HCl solution 4 M in 1,4-dioxane(1.2 eq) was added with the needle immersed in the mixture (exothermicreaction). The reaction mixture was heated with microwave during 2 h at160° C. The reaction mixture was taken up with a minimum of MeOH andwhen the residue was dissolved, it was transferred in mixture of AcOEtand saturated NaHCO₃ solution. The resulting solution was extracted andthe aqueous phase was washed with AcOEt (×2). The organic layers werecombined, washed with 0.01 M critic acid solution, saturated NaHCO₃solution, dried over Na₂SO₄ and concentrated to dryness under reducedpressure. Finally, the crude was purified by automated combi-flash toafford the good compound.

General Procedure 10

Halogenated-compound (1.0 eq), boronic acid (or boronate) (1.1 eq) andPd(PPh₃)₄ (10% mol) was added in microwave vessel (10-20 mL). The vialwas sealed with a cap and the system was purged with vacuum and placedunder N₂. Then, the solids were dissolved in mixture of Toluene/EtOH(4.5:2.0, 0.11 M) and purged with vacuum/N₂ one more time. Then, asolution of K₂CO₃ (3.0 eq) in H₂O (1.8 M) was added. The reactionmixture was stirred and heated overnight at 95° C. with oil bath. Thereaction mixture was filtered on plug of celite. The filtrate was waspoured with water and was extracted with AcOEt (×3). The organic layerswere combined, washed with brine, dried over Na₂SO₄ and evaporated underreduced pressure. The residue was taken up in DCM/TFA (5:5) for 2 h atr.t. The solvents were evaporated under reduced pressure. The residuewas then neutralized with saturated NaHCO₃ solution and extracted withAcOEt (×2). The organic layers were washed, dried and concentrated invacuo. The residue was precipitate in DCM or purified by automatedcombi-flash to afford the good compound.

2-1H-indol-3-yl)-4-methylquinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 5.6 13 547 CA 2-69 F6-11 (yield =62%) IC₅₀ (PSA) = No Data

  (Beige Solid) t_(R) (HPLC) = 3.20 min MS (ESI+) m/z = 259.1243 [(M +H)⁺] Mp = 168-180° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z =259.1230; found, 259.1237 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.63 (s,1H, H₁₄), 8.90-8.85 (m, 1H, H₂₀), 8.32 (d, J = 2.8 Hz, 1H, H₁₃),8.04-7.98 (m, 2H, H_(3, 6)), 7.94 (d, J = 0.9 Hz, 1H, H₉), 7.71 (ddd, J= 8.3, 6.9, 1.4 Hz, 1H, H₂), 7.53-7.44 (m, 2H, H_(1, 17)), 7.24-7.16 (m,2H, H_(18, 19)), 2.71 (d, J = 0.8 Hz, 3H, H₁₂). ¹³C NMR (101 MHz,DMSO-d₆): δ (ppm) = 155.74 (C₈-arom.), 148.21 (C₄-arom.), 143.61(C₁₀-arom.), 137.64 (C₁₅-arom.), 129.51 (C₂H-arom.), 129.39 (C₃H-arom.),127.98 (C₁₃H-arom.), 126.42 (C₅-arom.), 126.13 (C₁₆-arom.), 125.18(C₁H-arom.), 124.35 (C₆H-arom.), 123.12 (C₂₀H-arom.), 122.48(C₁₈H-arom.), 120.68 (C₁₉H- arom.), 119.90 (C₉H-arom.), 115.97(C₁₁-arom.), 112.16 (C₁₇H-arom.), 18.76 (C₁₂H₃).

2-(7-methoxy-1H-indol-1H-yl)-4-methylquinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.6 13 554 CA 2-87 F7-10 (yield =22%) IC₅₀ (PSA) = 0.67

  (Yellow Solid) t_(R) (HPLC) = 3.37 min MS (ESI+) m/z = 289.1336 [(M +H)⁺] Mp = 146-152° C. HRMS (ESI+): calculated for C₁₉H₁₇N₂O, m/z =289.1335; found, 289.1335 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.73 (s,1H, H₁₄), 8.45 (d, J = 8.0 Hz, 1H, H₂₀), 8.21 (d, J = 2.9 Hz, 1H, H₁₃),8.03-7.99 (m, 2H, H_(3, 6)), 7.95 (d, J = 0.8 Hz, 1H, H₉), 7.70 (ddd, J= 8.2, 6.8, 1.3 Hz, 1H, H₂), 7.50 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H, H₁),7.11 (t, J = 7.9 Hz, 1H, H₁₉), 6.79 (d, J = 7.5 Hz, 1H, H₁₈), 3.97 (s,3H, H₂₂), 2.70 (d, J = 0.8 Hz, 3H, H₁₂). ¹³C NMR (151 MHz, DMSO-d₆): δ(ppm) = 155.23 (C₈-arom.), 147.71 (C₄- arom.), 146.06 (C₁₇-arom.),143.11 (C₁₀-arom.), 129.00 (C₂H-arom.), 128.91 (C₃H-arom.), 127.23(C₁₅-arom.), 127.14 (C₁₆-arom.), 126.97 (C₁₃H-arom.), 125.95 (C₅-arom.),124.69 (C₁H-arom.), 123.85 (C₆H-arom.), 120.76 (C₁₉H- arom.), 119.52(C₉H-arom.), 116.09 (C₁₁-arom.), 115.37 (C₂₀H-arom.), 102.58(C₁₈H-arom.), 55.18 (C₂₂H₃), 18.24 (C₁₂H₃).

2-(1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.06 13 562 CA 2-128 F8-12 (yield= 46%) IC₅₀ (PSA) = 0.14

  (Beige Solid) t_(R) (HPLC) = 2-91 min MS (ESI+) m/z = 245.1073 [(M +H)⁺] Mp = 184-187° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z =245.1073; found, 245.1075 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.65 (s,1H, H₁₃), 8.88 (d, J = 8.5 Hz, 1H, H₁₉), 8.35 (d, J = 2.7 Hz, 1H, H₁₂),8.26 (d, J = 8.6 Hz, 1H, H₁₀), 8.o6 (d, J = 8.7 Hz, 1H, H₉), 8.04 (d, J= 8.3 Hz, 1H, H₃), 7.89 (d, J = 7.9 Hz, 1H, H₆), 7.72 (t, J = 7.6 Hz,1H, H₂), 7.51-7.46 (m, 2H, H_(1,16)), 7.24-7.18 (m, 2H, H_(17,18)). ¹³CNMR (101 MHz, DMSO-d₆): δ (ppm) = 155.56 (C₈-arom.), 147.75 C₄-arom.s),137.21 (C₁₄-arom.), 135.59 (C₁₀H-arom.), 129.34 (C₂H-arom.), 128.34(C₃H- arom.), 127.79 (C₆H-arom.), 127.61 (C₁₂H-arom.), 125.80(C₅-arom.), 125.58 (C₁₅- arom.), 124.88 (C₁H-arom.), 122.57(C₁₉H-arom.), 122.08 (C₁₇H-arom.), 120.31 (C₁₈H-arom.), 119.21(C₉H-arom.), 115.49 (C₁₁H-arom.), 111.73 (C₁₆H-arom.).

2-(7-fluoro-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.6 13 569 CA 3-45 F13-23Precipitate (yield = 34%) IC₅₀ (PSA) = Not Tested

  (Red Solid) t_(R) (HPLC) = 3.02 min MS (ESI+) m/z = 263.1009 [(M +H)⁺] Mp = 152-154° C. HRMS (ESI+): calculated for C₁₇H₁₂FN₂, m/z =263.0979; found, 263.0976 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 12.17 (s,1H, H₁₃), 8.71 (d, J = 8.0 Hz, 1H, H₁₉), 8.44 (d, J = 2.8 Hz, 1H, H₁₂),8.29 (d, J = 8.7 Hz, 1H, H₁₀), 8.10 (d, J = 8.7 Hz, 1H, H₉), 8.05 (d, J= 8.3 Hz, 1H, H₃), 7.91 (d, J = 7.5 Hz, 1H, H₆), 7.73 (t, J = 7.5 Hz,1H, H₂), 7.51 (t, J = 7.5 Hz, 1H, H₁), 7.21-7.15 (m, 1H, H₁₈), 7.06 (dd,J = 11.4, 7.8 Hz, 1H, H₁₇). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 155.50(C₈-arom.), 149.63 (d, J = 243.4 Hz, C₁₆-arom.), 148.13 (C₄-arom.),136.29 (C₁₀H-arom.), 129.92 (C₂H- arom.), 129.85 (d, J = 5.2 Hz,C₁₅-arom.), 129.18 (C₁₂H-arom.), 128.90 (C₃H- arom.), 128.14(C₆H-arom.), 126.41 (C₅-arom.), 125.63 (C₁H-arom.), 125.52 (d, J = 13.2Hz, C₁₄-arom.), 121.14 (d, J = 6.2 Hz, C₁₈H-arom.), 119.76 (C₉H-arom.),119.30 (d, J = 3.0 Hz, C₁₉H-arom.), 116.97 (d, J = 1.3 Hz, C₁₁-arom.),107.43 (d, J = 15.6 Hz, C₁₇H-arom.).

2-(7-ethyl-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.2 13 567 CA 3-46 P2 F6-13 (yield= 45%) IC₅₀ (PSA) = 0.23

  (Yellow Solid) t_(R) (HPLC) = 3.16 min MS (ESI+) m/z = 273.1719 [(M +H)⁺] Mp = 159-162° C. HRMS (ESI+): calculated for C₁₉H₁₇N₂, m/z =273.1386; found, 273.1389 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 11.63 (s,1H, H₁₃), 8.73 (d, J = 7.9 Hz, 1H, H₁₉), 8.34 (d, J = 2.9 Hz, 1H, H₁₂),8.25 (d, J = 8.7 Hz, 1H, H₁₀), 8.09 (d, J = 8.7 Hz, 1H, H₉), 8.03 (d, J= 8.4 Hz, 1H, H₃), 7.88 (d, J = 7.2 Hz, 1H, H₆), 7.71 (ddd, J = 8.3,7.0, 1.4 Hz, 1H, H₂), 7.48 (ddd, J = 7.5, 6.5, 1.0 Hz, 1H, H₁), 7.15 (t,J = 7.8 Hz, 1H, H₁₈), 7.05 (d, J = 6.9 Hz, 1H, H₁₇), 2.93 (q, J = 7.5Hz, 2H, H₂₀), 1.32 (t, J = 7.5 Hz, 3H, H₂₁). ¹³C NMR (126 MHz, DMSO-d₆):δ (ppm) = 156.14 (C₈-arom.), 148.27 (C₄- arom.), 136.38 (C₁₄-arom.),135.97 (C₁₀H-arom.), 129.76 (C₂H-arom.), 128.86 (C₃H-arom.), 128.07(C₆H-arom.), 127.98 (C₁₂H-arom.), 127.62 (C₁₆-arom.), 126.28 (C₅-arom.),126.00 (C₁₅-arom.), 125.30 (C₁H-arom.), 121.28 (C₁₇H- arom.), 121.08(C₁₈H-arom.), 120.74 (C₁₉H-arom.), 119.80 (C₉H-arom.), 116.39(C₁₁-arom.), 24.09 (C₂₀H₂), 15.01 (C₂₁H₃).

2-(2-methyl-1H-indol-3-quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 20.0 13 570 CA 3-47 F35-40 (yield= 29%) IC₅₀ (PSA) = Not Tested

  (Brown Solid) t_(R) (HPLC) = 2.91 min MS (ESI+) m/z = 259.1435 [(M +H)⁺] Mp = 67-75° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z =259.1230; found, 259.1230 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.48 (s,1H, H₁₃), 8.34 (d, J = 8.6 Hz, 1H, H₁₀), 8.21 (dd, J = 6.5, 2.4 Hz, 1H,H₁₉), 8.01 (d, J = 8.4 Hz, 1H, H₃), 7.94 (d, J = 7.6 Hz, 1H, H₆), 7.85(d, J = 8.6 Hz, 1H, H₉), 7.73 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H, H₂), 7.52(ddd, J = 8.0, 7.0, 1.1 Hz, 1H, H₁), 7.40 (dd, J = 6.4, 2.2 Hz 1H, H₁₆),7.15-7.11 (m, 2H, H_(17, 18)), 2.77 (s, 3H, H₂₀). ¹³C NMR (126 MHz,DMSO-d₆): δ (ppm) = 156.19 (C₈-arom.), 148.41 (C₄- arom.), 137.38(C₁₂-arom.), 136.27 (C₁₀H-arom.), 135.74 (C₁₄-arom.), 129.85(C₂H-arom.), 128.87 (C₃H-arom.), 128.13 (C₆H-arom.), 127.46 (C₁₅-arom.),125.97 (C₅-arom.), 125.58 (C₁H-arom.), 121.69 (C₉H-arom.), 121.53 (C₁₇H-arom.) 120.38 (C₁₈H-arom.), 120.18 (C₁₉H-arom.), 112.46 (C₁₁-arom.),111.34 (C₁₆H-arom.), 14.36 (C₂₀H₃).

2-(6-bromo-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 1.3 13 568 CA 3-49 F44-63Precipitate (yield = 46%) IC₅₀ (PSA) = 1.56

  (Yellow Solid) t_(R) (HPLC) = 3.29 min MS (ESI+) m/z = 323.0190,325.0174 [(M + H)⁺] Mp = 189-194° C. HRMS (ESI+): calculated forC₁₇H₁₂BrN₂, m/z = 323.0178, 325.0159; found, 323.0183, 325.0167 ¹H NMR(500 MHz, DMSO-d₆): δ (ppm) = 11.79 (s, 1H, H₁₃), 8.84 (d, J = 8.5 Hz,1H, H₁₉), 8.39 (d, J = 2.8 Hz, 1H, H₁₂), 8.28 (d, J = 8.7 Hz, 1H, H₁₀),8.05 (m, 2H, H_(3, 9)), 7.90 (d, J = 7.5 Hz, 1H, H₆), 7.72 (t, J = 7.5Hz, 1H, H₂), 7.67 (d, J = 1.6 Hz, 1H, H₁₆), 7.50 (t, J = 7.5 Hz, 1H,H₁), 7.34 (dd, J = 8.5, 1.8 Hz, 1H, H₁₈). ¹³C NMR (126 MHz, DMSO-d₆): δ(ppm) = 155.52 (C₈-arom.), 148.15 (C₄- arom.), 138.58 (C₁₄-arom.),136.27 (C₁₀H-arom.), 129.91 (C₂H-arom.), 129.11 (C₁₂H-arom.), 128.88(C₃H-arom.), 128.13 (C₆H-arom.), 126.37 (C₅- arom.), 125.59 (C₁H-arom.),125.11 (C₁₅-arom.), 124.82 (C₁₉H-arom.), 123.65 (C₁₈H-arom.), 119.57(C₉H-arom.), 116.11 (C₁₁-arom.), 115.31 (C₁₇- arom.), 114.82(C₁₆H-arom).

2-(1-methyl-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 1.1 13 571 CA 3-56 Precipitate(yield = 53%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 3.05 min MS (ESI+) m/z = 259.1355 [(M + H)⁺] Mp =175-179° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found,259.1232 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 8.88 (d, J = 8.5 Hz, 1H,H₁₉), 8.34 (s, 1H, H₁₂), 8.27 (d, J = 8.7 Hz, 1H, H₁₀), 8.03 (d, J = 8.3Hz, 1H, H₃), 7.98 (d, J = 8.7 Hz, 1H, H₉), 7.89 (d, J = 7.2 Hz, 1H, H₆),7.72 (t, J = 7.6 Hz, 1H, H₂), 7.54 (d, J = 7.5 Hz, 1H, H₁₆), 7.49 (t, J= 7.6 Hz, 1H, H₂), 7.29-7.26 (m, 2H, H_(17, 18)), 3.91 (s, 3H, H₂₀). ¹³CNMR (126 MHz, DMSO-d₆): δ (ppm) = 155.64 (C₈-arom.), 148.28 (C₄- arom.),138.16 (C₁₄-arom.), 136.21 (C₁₀H-arom.), 132.24 (C₁₂H-arom.), 129.88(C₂H-arom.), 128.84 (C₃H-arom.), 128.11 (C₆H-arom.), 126.43 (C₁₅-arom.),126.27 (C₅-arom.), 125.40 (C₁H-arom.), 123.16 (C₁₉H-arom.), 122.66(C₁₇H- arom.), 121.07 (C₁₈H-arom.), 119.50 (C₉H-arom.), 115.00(C₁₁-arom.), 110.58 (C₁₆H-arom.), 33.40 (C₂₀H₃-arom.).

2-(1H-indazol-1-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.7 13 572 CA 3-59 F11 (yield =25%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 4.44 min MS (ESI+) m/z = 246.1019 [(M + H)⁺] Mp = 91-96°C. HRMS (ESI+): calculated for C₁₆H₁₂N₃, m/z = 246.1026; found, 246.1028¹H NMR (500 MHz, CDCl₃): δ (ppm) = 9.18 (d, J = 8.5 Hz, 1H, H₁₆), 8.28(d, J = 9.0 Hz, 1H, H₉), 8.25-8.21 (m, 2H, H_(10, 11)), 8.11 (d, J = 8.4Hz, 1H, H₃), 7.82-7.77 (m, 2H, H_(6, 19)), 7.72 (ddd, J = 8.3, 7.0, 1.4Hz, 1H, H₂), 7.59 (ddd, J = 8.3, 7.0, 1.0 Hz, 1H, H₁₇), 7.48 (ddd, J =8.1, 7.0, 1.3 Hz, 1H, H₁), 7.32 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H, H₁₈).¹³C NMR (126 MHz, CDCl₃): δ (ppm) = 152.95 (C₈-arom.), 146.66 (C₄-arom.), 139.00 (C₄-arom.), 138.46 (C₁₀H-arom.), 137.18 (C₁₁H-arom.),130.05 (C₂H-arom.), 128.36 (C₃H-arom.), 128.22 (C₁₇H-arom.), 127.67(C₆H-arom.), 126.28 (C₅-arom.), 126.14 (C₁₅-arom.), 125.51 (C₁H-arom.),122.95 (C₁₈H- arom.), 120.82 (C₁₉H-arom.), 116.03 (C₁₆H-arom.), 113.48(C₉H-arom.).

2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.095 13 566 CA 3-67 Precipitate(yield = 48%) IC₅₀ (PSA) = 0.056

t_(R) (HPLC) = 3.10 min MS (ESI+) m/z = 259.1255 [(M + H)⁺] Mp =146-150° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found,259.1229 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 11.63 (s, 1H), 8.72 (d, J= 7.9 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.09(d, J = 8.7 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H),7.74-7.68 (m, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H),7.02 (d, J = 7.0 Hz, 1H), 2.54 (s, 3H). ¹³C NMR (126 MHz, DMSO-d₆): δ(ppm) = 156.14, 148.27, 137.19, 135.98, 129.77, 128.86, 128.08, 128.02,126.28, 125.82, 125.31, 123.10, 121.27, 120.98, 120.70, 119.79, 116.41,17.27.

2-(5-methyl-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 3.2 13 577 CA 3-73 Precipitate(yield = 55%) IC₅₀ (PSA) = 1.73

t_(R) (HPLC) = 3.12 min MS (ESI+) m/z = 259.1248 [(M + H)⁺] HRMS (ESI+):calculated for C₁₈H₁₅N₂, m/z = 259.1230; found, 259.1218 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 12.64 (s, 1H, H₁₃), 8.97 (s, 1H, H₁₂), 8.89 (d,J = 8.1 Hz, 1H, H₁₀), 8.58 (d, J = 8.2 Hz, 1H, H₃), 8.42 (d, J = 8.9 Hz,1H, H₉), 8.22 (d, J = 8.0 Hz, 1H, H₆), 8.10 (s, 1H, H₁₉), 8.02 (t, J =7.6 Hz, 1H, H₂), 7.77 (t, J = 7.5 Hz, 1H, H₁), 7.52 (d, J = 8.3 Hz, 1H,H₁₆), 7.18 (dd, J = 8.3, 0.9 Hz, 1H, H₁₇), 2.51 (s, 3H, H₂₀). ¹³C NMR =Done but unreadable and it was the same for every compound made withthis procedure

2-(6-fluoro-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.144 13 576 CA 3-75 Precipitate2(yield = 30%) IC₅₀ (PSA) = 0.048

t_(R) (HPLC) = 3.08 min MS (ESI+) m/z = 263.1223 [(M + H)⁺] Mp =259-266° C. HRMS (ESI+): calculated for C₁₇H₁₁FN₂Na, m/z = 285.0798;found, 285.0810 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 8.71 (s, 2H,H_(10, 12)), 8.49 (s, 1H, H₁₉), 8.31 (s, 2H, H_(3, 9)), 8.14 (s, 1H,H₆), 7.95 (s, 1H, H₂), 7.71 (s, 1H, H₁), 7.40 (d, J = 8.3 Hz, 1H, H₁₆),7.18 (t, J = 8.5 Hz, 1H, H₁₈). ¹³C NMR = Done but unreadable and it wasthe same for every compound made with this procedure, even protonspectra looked bad.

2-(6-(trifluoromethyl)-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 2.9 13 580 CA 3-78 Precipitate(yield = 8%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 3.50 min MS (ESI+) m/z = 313.0949 [(M + H)⁺] HRMS (ESI+):calculated for C₁₈H₁₂F₃N₂, m/z = 313.0947; found, 313.0947 ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 8.83 (s, 1H, H₁₂), 8.75 (s, 2H, H_(10, 19)),8.31 (s, 2H, H_(3, 9)), 8.11 (s, 1H, H₆), 7.93 (s, 2H, H_(2, 16)), 7.70(s, 1H, H₁), 7.58 (d, J = 7.9 Hz, 1H, H₁₈). ¹³C NMR Done but unreadableand it was the same for every compound made with this procedure, evenproton spectra looked bad.

2-(7-methyl-1H-indazol-1-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 3.5 13 575 CA 3-90 F4-12Precipitate (yield = 21%) IC₅₀ (PSA) = 1.36

t_(R) (HPLC) = 4.54 min MS (ESI+) m/z = 260.1176 [(M + H)⁺] Mp =147-152° C. HRMS (ESI+): calculated for C₁₇H₁₄N₃, m/z = 260.1182; found,260.1172 ¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 9.42 (s, 1H, H₁₁), 8.69(d, J = 8.8 Hz, 1H, H₁₀), 8.49 (d, J = 8.8 Hz, 1H, H₉), 8.12 (d, J = 8.0Hz, 1H, H₆), 8.09 (d, J = 8.5 Hz, 1H, H₃), 7.89 (ddd, J = 8.0, 6.5, 1.0Hz, 1H, H₂), 7.71-7.65 (m, 2H, H_(1, 9)), 7.14 (d, J = 6.6 Hz, 1H, H₁₇),7.05 (dd, J = 8.3, 6.7 Hz, 1H, H₁₈), 2.62 (s, 3H, H₂₀). ¹³C NMR (126MHz, DMSO-d₆): δ (ppm) = 150.74 (C₁₄-arom.), 150.56 (C₈- arom.), 146.38(C₄-arom.), 140.60 (C₁₀H-arom.), 131.47 (C₂H-arom.), 128.69 C₆H-arom.),128.66 (C₃H-arom.), 127.92 (C₅-arom.), 127.89 (C₁₆-arom.), 127.33(C₁H-arom.), 126.89 (C₁₇H-arom.), 123.64 (C₁₈H-arom.), 122.62 (C₁₅-arom.), 121.65 (C₁₁H-arom.), 119.49 (C₁₉H-arom.), 113.50 (C₉H-arom.),17.22 (C₂₀H₃).

2-(6-(benzyloxy)-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 5.3 13 589 CA 3-94 Precipitate(yield = 20%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 3.66 min MS (ESI+) m/z = 351.1707 [(M + H)⁺] Mp =264-269° C. HRMS (ESI+): calculated for C₂₄H₁₉N₂O, m/z = 351.1492;found, 351.1494 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.50 (s, 1H, H₁₃),8.85 (s, 2H, H₁₀), 8.52 (d, J = 5.6 Hz, 1H, H₃), 8.37 (d, J = 8.7 Hz,1H, H₉), 8.20 (d, J = 7.2 Hz, 2H, H_(6, 19)), 8.00 (t, J = 7.3 Hz, 1H,H₂), 7.75 (t, J = 7.3 Hz, 1H, H₁), 7.51 (d, J = 7.2 Hz, 2H, H_(22, 26)),7.42 (t, J = 7.4 Hz, 2H, H_(23, 25)), 7.35 (t, J = 7.3 Hz, 1H, H₂₄),7.19 (d, J = 1.7 Hz, 1H, H₁₆), 7.06 (dd, J = 8.8, 2.0 Hz, 1H, H₁₈), 5.21(s, 2H, H₂₇). ¹³C NMR Done but unreadable and it was the same for everycompound made with this procedure, even proton spectra looked bad.

3-(pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 4.9 13 581 CA 3-105 Purified(yield = 64%) IC₅₀ (PSA) = Not Tested

t_(R) (HPLC) = 1.45 min MS (ESI+) m/z = 196.0861 [(M + H)⁺] Mp = 71-80°C. HRMS (ESI+): calculated for C₁₂H₁₀N₃, m/z = 196.0869; found, 196.0862¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 12.21 (s, 1H, H₁₃), 8.99 (s, 1H,H₃), 8.90 (s, 1H, H₉), 8.49 (s, 1H, H₂), 8.25 (s, 1H, H₇), 8.21 (s, 1H,H₁₄), 8.16- 8.12 (m, 1H, H₅), 7.94 (d, J = 4.0 Hz, 1H, H₁₂), 7.48 (dd, J= 7.7, 4.8 Hz, 1H, H₆). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 147.26(C₃H-arom.), 146.80 (C₂H- arom.), 137.78 (C₇H-arom.), 134.44(C₉H-arom.), 133.82 (C₁₀-arom.), 133.41 (C₅H-arom.), 130.47 (C₄-arom.),129.35 (C₁₁-arom.), 128.95 (C₁₄H-arom.), 123.95 (C₆H-arom.), 113.91(C₁₂H-arom.), 111.96 (C₁₅-arom.).

3-(pyridin-3-yl)-1H-indazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = No Data 13 590 CA 3-106Precipitate (yield = 45%) IC₅₀ (PSA) = No Data

t_(R) (HPLC) = 2.53 min MS (ESI+) m/z = 196..0889 [(M + H)⁺] Mp =176-179° C. HRMS (ESI+): calculated for C₁₂H₁₀N₃, m/z = 196.0869; found,196.0871 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 9.21 (d, J = 1.5 Hz, 1H,H₅), 8.62 (dd, J = 4.7, 1.6 Hz, 1H, H₂), 8.38 (td, J = 8.4, 1.8 Hz, 1H,H₃), 8.12 (d, J = 8.2 Hz, 1H, H₁₂), 7.64 (d, J = 8.4 Hz, 1H, H₉), 7.56(ddd, J = 7.9, 4.8, 0.7 Hz, 1H, H₁), 7.45 (ddd, J = 8.4, 7.2, 0.6 Hz,1H, H₈), 7.25 (ddd, J = 7.8, 6.6, 0.6 Hz, 1H, H₈). ¹³C NMR (151 MHz,DMSO-d₆): δ (ppm) = 148.59 (C₂H-arom.), 147.42 (C₅H-arom.), 141.50(C₁₀-arom.), 140.45 (C₄-arom.), 133.90 (C₃H-arom.), 129.63 (C₁₅-arom.),126.35 (C₈H-arom.), 124.02 (C₁H-arom.), 121.41 (C₇H-arom.), 120.43(C₁₂H-arom.), 120.06 (C₁₁-arom.), 110.72 (C₉H-arom.).

2-(7-bromo-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 0.052 13 582 CA 3-107 F9-17Precipitate (yield = 20%) IC₅₀ (PSA) = 0.041

t_(R) (HPLC) = 3.25 min MS (ESI+ ) m/z = 323.0177, 325.0158 [(M + H)⁺]Mp = 178-180° C. HRMS (ESI+): calculated for C₁₇H₁₂BrN₂, m/z = 323.0178,325.0159; found, 323.0172, 325.0153 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) =11.87 (s, 1H, H₁₃), 8.94 (d, J = 7.9 Hz, 1H, H₁₉), 8.42 (d, J = 2.8 Hz,1H, H₁₂), 8.29 (d, J = 8.6 Hz, 1H, H₁₀), 8.13 (d, J = 8.7 Hz, 1H, H₉),8.06 (d, J = 8.4 Hz, 1H, H₃), 7.91 (d, J = 8.0 Hz, 1H, H₆), 7.73 (ddd, J= 8.4, 7.2, 1.2 Hz, 1H, H₂), 7.51 (ddd, J = 7.8, 6.6, 0.6 Hz, 1H, H₁),7.45 (dd, J = 7.5, 0.5 Hz, 1H, H₁₇), 7.17 (t, J = 7.8 Hz, 1H, H₁₈). ¹³CNMR (151 MHz, DMSO-d₆): δ (ppm) = 155.00 (C₈-arom.), 147.65 (C₄- arom.),135.81 (C₁₀H-arom.), 135.51 (C₁₄H-arom.), 129.43 (C₂H-arom.), 128.78(C₁₂H-arom.), 128.46 (C₃H-arom.), 127.65 (C₆H-arom.), 127.36 (C₁₅-arom.), 125.96 (C₅-arom.), 125.19 (C₁H-arom.), 124.73 (C₁₇H-arom.),122.17 (C₁₉H-arom.), 121.76 (C₁₈H-arom.), 119.31 (C₉H-arom.), 116.67(C₁₁-arom.), 104.34 (C₁₆-arom.).

2-(1H-pyrrolo[2,3-c]pyridin-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.1 13 583 CA 3-109 F22-31Precipitate (yield = 19%) IC₅₀ (PSA) = 0.93

t_(R) (HPLC) = 2.52 min MS (ESI+) m/z = 246.1028 [(M + H)⁺] Mp = <270°C. HRMS (ESI+): calculated for C₁₆H₁₂N₃, m/z = 246.1026; found, 246.1017¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 12.12 (s, 1H, H₁₇), 8.85 (d, J =0.8 Hz, 1H, H₁₃), 8.72 (dd, J = 5.4, 0.9 Hz, 1H, H₁₆), 8.58 (d, J = 2.4Hz, 1H, H₁₈), 8.31 (m, 2H, H_(10, 11)), 8.09 (d, J = 8.7 Hz, 1H, H₉),8.07 (d, J = 8.3 Hz, 1H, H₃), 7.92 (d, J = 8.0 Hz, 1H, H₆), 7.74 (ddd, J= 8.3, 6.9, 1.4 Hz, 1H, H₂), 7.52 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H, H₁).¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 154.73 (C₈-arom.), 147.73 (C₄-arom.), 139.35 (C₁₁H-arom.), 136.01 (C₁₀H-arom.), 134.88 (C₁₃H-arom.),134.37 (C₁₄-arom.), 130.89 (C₁₈H-arom.), 129.92 (C₁₅-arom.), 129.51(C₂H-arom.), 128.46 (C₃H-arom.), 127.69 (C₆H-arom.), 125.97 (C₅-arom.),125.24 (C₁H- arom.), 119.03 (C₉H-arom.), 116.77 (C₁₆H-arom.), 115.22(C₁₉-arom.).

tert-butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

LabBook Code Intermediate CA 3-111 F1-14 (yield = 86%)

t_(R) (HPLC) = 4.66 min MS (ESI+) m/z = 345.0074 [(M + H)⁺] ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 8.44 (dd, J = 4.7, 1.5 Hz, 1H, H₂), 8.03 (s,1H, H₈), 7.79 (dd, J = 7.9, 1.6 Hz, 1H, H₆), 7.39 (dd, J = 7.9, 4.7 Hz,1H, H₁), 1.62 (s, 9H, H_(13, 14, 15)). ¹³C NMR (101 MHz, DMSO-d₆): δ(ppm) = 147.14 (C₁₆ = O), 147.04 (C₄- arom.), 146.16 (C₂H-arom.), 131.54(C₈H-arom.), 130.04 (C₆H-arom.), 125.25 (C₅-arom.), 120.04 (C₁H-arom.),84.57 (C₁₂-(CH₃)₃), 63.79 (C₉-arom.), 28.08 (C_(13, 14, 15)H₃).

3-(1H-pyrrolo[3,2-c]pyridin-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 637 CA 3-115Precipitate (yield = 51%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 2.22 min MS (ESI+) m/z = 246.1020 [(M + H)⁺] Mp =233-239° C. HRMS (ESI+): calculated for C₁₆H₁₂N₃, m/z = 246.1026; found,246.1016 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.04 (s, 1H, H₁₃), 9.43(s, 1H, H₁₂), 9.37 (d, J = 2.3 Hz, 1H, H₅), 8.76 (d, J = 1.9 Hz, 1H,H₃), 8.31 (d, J = 5.7 Hz, 1H, H₈), 8.19 (d, J = 1.7 Hz, 1H, H₁₄), 8.13(d, J = 7.6 Hz, 1H, H₁₉), 8.03 (d, J = 8.3 Hz, 1H, H₁₆), 7.72 (ddd, J =8.4, 6.9, 1.4 Hz, 1H, H₁₇), 7.63 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H, H₁₈),7.51 (dd, J = 5.7, 0.7 Hz, 1H, H₉). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm)= 150.40 (C₅H-arom.), 146.38 (C₂- arom.), 142.88 (C₁₂H-arom.), 141.29(C₈H-arom.), 140.94 (C₁₀-arom.), 131.31 (C₃H-arom.), 129.08(C₁₇H-arom.), 129.04 (C₁₆H-arom.), 128.62 (C₁- arom.), 128.60(C₁₉H-arom.), 128.35 (C₄-arom.), 127.31 (C₁₈H-arom.), 126.19(C₁₄H-arom.), 122.63 (C₁₁-arom.), 112.66 (C₁₅-arom.), 107.80 (C₉H-arom.).

3-(5-bromo-2-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 638 CA 3-116Precipitate (yield = quant.) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 2.91 min MS (ESI+) m/z = 303.0118, 305.0099 [(M + H)⁺] Mp= <270° C. HRMS (ESI+): calculated for C₁₄H₁₂BrN₂O, m/z = 303.0128,305.0108; found, 303.0119, 305.0100 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) =12.03 (s, 1H, H₁₃), 8.82 (d, J = 0.6 Hz, 1H, H₁₂), 8.20 (d, J = 5.7 Hz,1H, H₈), 7.70 (d, J = 2.0 Hz, 1H, H₁₄), 7.65 (d, J = 2.5 Hz, 1H, H₂),7.47 (dd, J = 8.8, 2.6 Hz, 1H, H₆), 7.44 (dd, J = 5.7, 1.0 Hz, 1H, H₉),7.12 (d, J = 8.8 Hz, 1H, H₃), 3.82 (s, 3H, H₁₈). ¹³C NMR (101 MHz,DMSO-d₆): δ (ppm) = 155.97 (C₅-arom.), 143.25 (C₁₂H-arom.), 140.41(C₈H-arom.), 140.06 (C₁₀-arom.), 132.27 (C₃H- arom.), 130.31(C₆H-arom.), 127.00 (C₁₄H-arom.), 126.07 (C₄-arom.), 123.24 (C₁₁-arom.),114.24 (C₂H-arom.), 112.46 (C₁-arom.), 110.90 (C₁₅-arom.), 107.57(C₉H-arom.), 56.13 (C₁₈H₃).

3-(7-bromo-1H-indol-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.13 13 653 CA 3-123 Precipitate(yield = 39%) IC₅₀ (PSA) = 0.29

t_(R) (HPLC) = 3.79 min MS (ESI+) m/z = 323.0176, 325.0157 [(M + H)⁺] Mp= 217-223° C. HRMS (ESI+): calculated for C₁₇H₁₂BrN₂, m/z = 323.0178,325.0159; found, 323.0179, 325.0160 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) =11.86 (s, 1H, H₁₃), 9.33 (d, J = 2.2 Hz, 1H, H₅), 8.66 (d, J = 1.9 Hz,1H, H₃), 8.12-8.06 (m, 3H, H_(12,14,19)), 8.03 (d, J = 8.3 Hz, 1H, H₁₆),7.72 (t, J = 8.2 Hz, 1H, H₁₇), 7.63 (t, J = 7.4 Hz, 1H, H₁₈), 7.47 (d, J= 7.5 Hz, 1H, H₈), 7.14 (t, J = 7.8 Hz, 1H, H₇). ¹³C NMR (101 MHz,DMSO-d₆): δ (ppm) = 150.63 (C₅H-arom.), 146.32 (C₂-arom.), 135.72(C₁₀-arom.), 131.21 (C₃H-arom.), 129.11 (C₁₇H-arom.), 128.99 (C₁-arom.),128.86 (C₁₂H-arom.), 128.57 (C₄-arom.), 128.48 (C₁₉H- arom.), 127.28(C₁₈H-arom.), 127.19 (C₁₁-arom.), 126.42 (C₁₄H-arom.), 125.01(C₈H-arom.), 121.96 (C₇H-arom.), 119.28 (C₁₂H-arom.), 114.08 (C₁₅-arom.), 105.30 (C₉-arom.).

3-(7-methyl-1H-indol-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.92 13 654 CA 3-125 Precipitate(yield = 56%) IC₅₀ (PSA) = 0.16

t_(R) (HPLC) = 3.43 min MS (ESI+) m/z = 259.1236 [(M + H)⁺] Mp =215-219° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found,259.1234 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.59 (s, 1H, H₁₃), 9.34(d, J = 2.3 Hz, 1H, H₅), 8.62 (d, J = 2.1 Hz, 1H, H₃), 8.07 (m, 2H,H₁₄,₁₉), 8.01 (d, J = 8.4 Hz, 1H, H₁₆), 7.92 (d, J = 7.9 Hz, 1H, H₁₂),7.69 (td, J = 8.4, 1.5 Hz, 1H, H₁₇), 7.61 (td, J = 8.1, 1.2 Hz, 1H,H₁₈), 7.12 (t, J = 7.6 Hz, 1H, H₇), 7.03 (d, J = 7.0 Hz, 1H, H₈), 2.54(s, 3H, H₂₀). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.68 (C₅H-arom.),146.10 (C₂- arom.), 136.96 (C₁₀-arom.), 130.41 (C₃H-arom.), 129.74(C₁₇H-arom.), 129.08 (C₁₆-arom.), 128.72 (C₁-arom.), 128.64 (C₄-arom.),128.37 (C₁₉H- arom.), 127.19 (C₁₈H-arom.), 125.16 (C₁₁-arom.), 125.01(C₁₄H-arom.), 122.86 (C₈H-arom.), 121.80 (C₉-arom.), 120.77 (C₇H-arom.),117.24 (C₁₂H- arom.), 113.06 (C₁₅H-arom.), 17.30 (C₂₀H₃).

7-methyl-3-(pyridin-3-yl)-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.66 13 655 CA 3-127 F5Precipitate (yield = 25%) IC₅₀ (PSA) = 0.61

t_(R) (HPLC) = 2.69 min MS (ESI+) m/z = 209.1076 [(M + H)⁺] Mp =164-166° C. HRMS (ESI+): calculated for C₁₄H₁₃N₂, m/z = 209.1073; found,209.1075 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.49 (s, 1H, H₁₃), 8.94(d, J = 1.7 Hz, 1H, H₅), 8.43 (dd, J = 4.7, 1.5 Hz, 1H, H₂), 8.09 (dt, J= 8.0, 1.9 Hz, 1H, H₃), 7.84 (d, J = 2.7 Hz, 1H, H₁₄), 7.70 (d, J = 7.8Hz, 1H, H₁₂), 7.44 (ddd, J = 7.9, 4.8, 0.6 Hz, 1H), 7.08-6.96 (m, 2H,H_(7,8)), 2.51 (s, 3H, H₁₆). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =147.81 (C₅H-arom.), 146.63 (C₂H- arom.), 136.86 (C₁₀-arom.), 133.75(C₃H-arom.), 132.32 (C₄-arom.), 124.99 (C₁₁-arom.), 124.40 (C₁₄H-arom.),124.28 (C₁H-arom.), 122.66 (C₈H-arom.), 121.74 (C₉-arom.), 120.62(C₇H-arom.), 116.87 (C₁₂H-arom.), 113.02 (C₁₅- arom.), 17.28 (C₁₆H₃).

tert-butyl 7-(benzyloxy)-3-iodo-1H-indole-1-carboxylate

LabBook Code Intermediate CA 3-128 F1-4 Precipitate (yield = 88%)

t_(R) (HPLC) = 5.03 min MS (ESI+) m/z = 450.0575 [(M + H)⁺] ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 7.84 (s, 1H, H₈), 7.57-7.52 (m, 2H,H_(14, 18)), 7.40-7.27 (m, 4H, H_(1, 15, 16, 17)), 7.11 (d, J = 7.6 Hz,1H, H₂), 6.98 (dd, J = 7.8, 0.8 Hz, 1H, H₆), 5.25 (s, 2H, H₁₂), 1.50 (s,9H, H_(21, 22, 23)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 148.11(C₂₄O), 147.18 (C₃-arom.), 137.44 (C₁₃-arom.), 134.78 (C₅-arom.), 132.89(C₈H-arom.), 128.67 (C_(15, 17)H- arom.), 128.16 (C₁₆H-arom.), 127.88(C_(14, 18)H-arom.), 124.89 (C₁H-arom.), 124.45 (C₄-arom.), 114.11(C₆H-arom.), 109.43 (C₂H-arom.), 84.39 (C₂₀(CH₃)₃), 70.58 (C₁₂H₂), 65.68(C₉-arom.), 27.68 (C_(21, 22, 23)H₃).

5,8-dibromo-2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 679 CA 3-137 F24-30Precipitate (yield = 20%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 5.30 min MS (ESI+) m/z = 414.9448, 416.9430, 418.9416[(M + H)⁺] Mp = 218-221° C. HRMS (ESI+): calculated for C₁₈H₁₃Br₂N₂, m/z= 414.9440, 416.942., 418.9402; found, 414.9448, 416.9430, 418.9415 ¹HNMR (400 MHz, DMSO-d₆): δ (ppm) = 11.84 (s, 1H, H₁₃), 9.01 (d, J = 7.9Hz, 1H, H₁₉), 8.54 (d, J = 2.9 Hz, 1H, H₁₂), 8.38 (d, J = 9.0 Hz, 1H,H₁₀), 8.33 (d, J = 9.0 Hz, 1H, H₉), 8.04 (d, J = 8.1 Hz, 1H, H₂), 7.73(d, J = 8.1 Hz, 1H, H₁), 7.16 (t, J = 7.6 Hz, 1H, H₁₈), 7.05 (d, J = 7.1Hz, 1H, H₁₇), 2.55 (s, 3H, H₂₀). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =157.55 (C₈-arom.), 145.79 (C₄- arom.), 137.28 (C₁₄-arom.), 135.21(C₁₀H-arom.), 133.70 (C₂H-arom.), 129.80 (C₁₂H-arom.), 129.33(C₁H-arom.), 126.24 (C₅H-arom.), 125.67 (C1₅-arom.), 124.03 (C₃-arom.),123.58 (C₁₇H-arom.), 122.06 (C₉H-arom.), 121.65 (C₁₈H- arom.), 121.42(C₁₆-arom.), 121.18 (C₆-arom., C₁₉H-arom.), 115.73 (C₁₁-arom.), 17.24(C₂₀H₃).

5-bromo-2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 678 CA 3-139 F15-21Precipitate (yield = 21%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 4.55 min MS (ESI+) m/z = 337.0363, 339.0354 [(M + H)⁺] Mp= 200-204° C. HRMS (ESI+): calculated for C₁₈H₁₄BrN₂, m/z = 337.0335,339.0316; found, 337.0345, 339.0331 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) =11.74 (s, 1H, H₁₃), 8.69 (d, J = 8.0 Hz, 1H, H₁₉), 8.42 (d, J = 3.0 Hz,1H, H₁₂), 8.36 (dd, J = 9.0, 0.7 Hz, 1H, H₁₀), 8.23 (d, J = 9.0 Hz, 1H,H₉), 8.06 (dt, J = 8.4, 0.9 Hz, 1H, H₁), 7.81 (dd, J = 7.5, 1.0 Hz, 1H,H₃), 7.64 (dd, J = 8.4, 7.6 Hz, 1H, H₂), 7.13 (t, J = 7.6 Hz, 1H, H₁₈),7.03 (d, J = 7.0 Hz, 1H, H₁₇), 2.54 (s, 3H, H₂₀). ¹³C NMR (101 MHz,DMSO-d₆): δ (ppm) = 156.97 (C₈-arom.), 149.20 (C₄- arom.), 137.24(C₁₄-arom.), 134.47 (C₁₀H-arom.), 130.54 (C₂H-arom.), 129.10(C₁H-arom.), 129.01 (C₃H-arom.), 128.88 (C₁₂H-arom.), 125.74 (C₅-arom.),125.10 (C₁₅-arom.), 123.32 (C₁₇H-arom.), 121.45 (C₉H-arom.), 121.43(C₁₆- arom.), 121.37 (C₆-arom.), 121.24 (C₁₈H-arom.), 120.60(C₁₉H-arom.), 115.71 (C₁₁-arom.), 17.25 (C₂₀H₃).

3-iodo-7-methyl-1-tosyl-1H-indole

LabBook Code Intermediate CA 3-140 P1-3 (yield = 48%)

t_(R) (HPLC) = 5.50 min MS (ESI+) m/z = 411.9835 [(M + H)⁺] ¹H NMR (500MHz, DMSO-d₆): δ (ppm) = 8.07 (s, 1H, H₈), 7.68 (d, J = 8.3 Hz, 2H,H_(13, 17)), 7.41 (d, J = 8.1 Hz, 2H, H_(14, 16)), 7.29-7.21 (m, 2H,H_(6, 1)), 7.17 (d, J = 6.7 Hz, 1H, H₂), 2.49 (s, 3H, H₁₁), 2.35 (s, 3H,H₁₈). ¹³C NMR (126 MHz, DMSO-d₆): δ (ppm) = 145.86 (C₁₅-arom.), 135.85(C₁₂- arom.), 134.57 (C₅-arom.), 134.23 (C₄-arom.), 133.76 (C₈H-arom.),130.85 (C_(14, 16)H-arom.), 129.76 (C₂H-arom.), 126.92(C_(13, 17)H-arom.), 125.12 (C₁H- arom.), 124.81 (C₃-arom.) 120.38(C₆H-arom.), 69.54 (C₉-arom.), 21.53 (C₁₈H₃), 21.47 (C₁₁H₃).

8-bromo-2-(7-methyl-1H-indol-3-yl)quinoline (Procedure 9)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.156 13 677 CA 3-141 F34-54Precipitate (yield = 20%) IC₅₀ (PSA) = 0.11

t_(R) (HPLC) = 5.03 min MS (ESI+) m/z = 337.0361, 339.0345 [(M + H)⁺] Mp= 214-217° C. HRMS (ESI+): calculated for C₁₈H₁₄BrN₂, m/z = 337.0335,339.0316; found, 337.0341, 339.0324 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) =11.72 (s, 1H, H₁₃), 9.04 (d, J = 8.0 Hz, 1H, H₁₉), 8.47 (d, J = 3.0 Hz,1H, H₁₂), 8.30 (d, J = 8.8 Hz, 1H, H₁₀), 8.20 (d, J = 8.7 Hz, 1H, H₉),8.09 (dd, J = 7.5, 1.3 Hz, 1H, H₂), 7.92 (dd, J = 8.1, 1.2 Hz, 1H, H₆),7.39 (t, J = 7.8 Hz, 1H, H₁), 7.14 (t, J = 7.4 Hz, 1H, H₁₈), 7.03 (d, J= 7.0 Hz, 1H, H₁₇), 2.54 (s, 3H, H₂₀). ¹³C NMR (101 MHz, DMSO-d₆): δ(ppm) = 156.88 (C₈-arom.), 144.96 (C₄- arom.), 137.23 (C₁₄-arom.),136.61 (C₁₀H-arom.), 133.25 (C₂H-arom.), 128.92 (C₁₂H-arom.), 128.20(C₆H-arom.), 127.68 (C₅-arom.), 125.91 (C₁H-arom.), 125.77 (C₁₅-arom.),123.97 (C₃-arom.), 123.36 (C₁₇H-arom.), 121.38 (C₁₈H- arom.), 121.33(C₁₉H-arom.), 121.23 (C₁₆-arom.), 120.45 (C₉H-arom.), 116.31(C₁₁-arom.), 17.25 (C₂₀H₃).

3-(naphthalen-2-yl)-1H-pyrrolo[2,3-c]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.45 13 675 CA 3-144 Precipitate(yield = 83%) IC₅₀ (PSA) = 0.468

t_(R) (HPLC) = 3.26 min MS (ESI+) m/z = 245.1334 [(M + H)⁺] Mp =243-247° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z = 245.1073; found,245.1079 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.99 (s, 1H, H₁₃), 8.86(s, 1H, H₉), 8.27 (s, 1H, H₃), 8.25 (d, J = 5.2 Hz, 1H, H₇), 8.17 (s,1H, H₁₄), 8.05 (dd, J = 5.6, 1.0 Hz, 1H, H₁₂), 8.02 (d, J = 8.1 Hz, 1H,H₁₉), 8.00-7.90 (m, 3H, H_(5,6,16)), 7.53 (ddd, J = 8.1, 6.8, 1.4 Hz,1H, H₁₈), 7.47 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H, H₁₇). ¹³C NMR (101 MHz,DMSO-d₆): δ (ppm) = 139.14 (C₇H-arom.), 135.56 (C₉H- arom.), 134.64(C₁₀-arom.), 134.14 (C₁-arom.), 132.82 (C₄-arom.), 131.87 (C₂- arom.),129.56 (C₁₁-arom.), 128.76 (C₆H-arom.), 128.43 (C₁₄H-arom.), 128.18(C₁₉H-arom.), 127.96 (C₁₆H-arom), 126.72 (C₁₈H-arom.), 126.01 (C₁₇H-arom.), 125.73 (C₅H-arom.) 124.12 (C₃H-arom.), 115.47 (C₁₅-arom.),114.55 (C₁₂H-arom.).

3-(naphthalen-2-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.053 13 676 CA 3-146 Precipitate(yield = 61%) IC₅₀ (PSA) = 0.034

t_(R) (HPLC) = 4.50 min MS (ESI+) m/z = 245.1077 [(M + H)⁺] Mp =207-211° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z = 245.1073; found,245.1077 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.01 (s, 1H, H₁₃), 8.50(dd, J = 8.0, 1.1 Hz, 1H, H₁₂), 8.32 (dd, J = 4.6, 1.5 Hz, 1H, H₈), 8.27(s, 1H, H₃), 8.06 (d, J = 2.7 Hz, 1H, H₁₄), 8.00 (d, J = 8.0 Hz, 1H,H₁₉), 7.97-7.92 (m, 2H, H₅, ₆), 7.91 (d, J = 8.0 Hz, 1H, H₁₆), 7.52(ddd, J = 8.2, 6.9, 1.4 Hz, 1H, H₁₈), 7.47 (ddd, J = 8.0, 6.9, 1.3 Hz,1H, H₁₇), 7.22 (dd, J = 8.0, 4.6 Hz, 1H, H₇). ¹³C NMR (101 MHz,DMSO-d₆): δ (ppm) = 149.69 (C₁₀-arom.), 143.50 (C₈H- arom.), 134.16(C₁-arom.), 133.12 (C₄-arom.), 131.85 (C₂-arom.), 128.70 (C₆H- arom.),128.31 (C₁₂H-arom.), 128.17 (C₁₉H-arom.), 127.94 (C₁₆H-arom.) 126.68(C₁₈H-arom.), 125.89 (C₁₇H-arom.), 125.66 (C₅H-arom.), 124.90(C₁₄H-arom.), 123.88 (C₃H-arom.), 117.81 (C₁₁-arom.), 116.62(C₇H-arom.), 114.55 (C₁₅-arom.).

2-(5-bromo-1H-indol-3-yl)quinoline

VPC Number LabBook Code IC₅₀ (eGFP) = 2.6 13 683 CA 3-147 F36-46Precipitate (yield = 39%) IC₅₀ (PSA) = 1.906

t_(R) (HPLC) = 3.60 min MS (ESI+) m/z = 323.0169, 325.0153 [(M + H)⁺] Mp= 200-203° C. HRMS (ESI+): calculated for C₁₇H₁₂BrN₂, m/z = 323.0178;325.0159; found, 323.0184, 325.0169 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) =11.86 (s, 1H, H₁₃), 9.06 (dd, J = 2.0 Hz, 1H, H₁₉), 8.42 (d, J = 2.8 Hz,1H, H₁₂), 8.27 (d, J = 8.5 Hz, 1H, H₁₀), 8.05 (d, J = 8.8 Hz, 1H, H₉),8.02 (d, J = 9.0 Hz, 1H, H₃), 7.89 (dd, J = 8.1, 1.2 Hz, 1H, H₆), 7.72(ddd, J = 8.4, 6.9, 1.5 Hz, 1H, H₆), 7.50 (ddd, J = 8.0, 6.9, 1.2 Hz,1H, H₁), 7.45 (dd, J = 8.4, 0.4 Hz, 1H, H₁₇), 7.34 (dd, J = 8.6, 2.0 Hz,1H, H₁₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 155.03 (C₈-arom.),147.62 (C₄- arom.), 135.92 (C₁₀H-arom.), 135.83 (C₁₄-arom.), 129.50(C₂H-arom.), 129.15 (C₁₂H-arom.), 128.36 (C₃H-arom.), 127.67(C₆H-arom.), 127.30 (C₁₅-arom.), 125.88 (C₅-arom.), 125.12 (C₁H-arom.),124.71 (C₁₉H-arom.), 124.62 (C₁₇H- arom.), 119.07 (C₉H-arom.), 115.02(C₁₁-arom.), 113.79 (C₁₈-arom.), 113.07 (C₁₆H- arom.).

3-(1H-indazol-3-yl)quinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.4 13 684 CA 4-13 F3-5 (yield =46%) IC₅₀ (PSA) = 6.609

t_(R) (HPLC) = 3.59 min MS (ESI+) m/z = 246.1322 [(M + H)⁺] Mp =212-215° C. HRMS (ESI+): calculated for C₁₆H₁₂N₃, m/z = 246.1026; found,246.1027 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 13.53 (s, 1H, H₁₃), 9.60(dd, J = 2.2 Hz, 1H, H₅), 8.98 (d, J = 2.0 Hz, 1H, H₃), 8.33 (d, J = 8.2Hz, 1H, H₁₂), 8.21 (d, J = 7.9 Hz, 1H, H₁₉), 8.09 (d, J = 8.3 Hz, 1H,H₁₆), 7.8.79 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H, H₁₇), 7.71-7.66 (m, 2H,H_(9, 18)), 7.48 (t, J = 7.4 Hz, 1H, H₈), 7.31 (t, J = 7.5 Hz, 1H, H₇).¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 149.67 (C₅H-arom.), 147.27 (C₂-arom.), 142.03 (s C₁₀-arom.), 141.01 (C₁-arom.), 132.67 (C₃H-arom.),129.94 C₁₇H-arom.), 129.20 (C₁₆H-arom.), 129.01 (C₁₉H-arom.), 128.24(C₄-arom.), 127.52 (C₁₈H-arom.), 127.29 (C₁₅-arom.), 126.96 (C₈H-arom.),121.96 (C₇H- arom.), 121.23 (C₁₂H-arom.), 120.81 (C₁₁-arom.), 111.26(C₉H-arom.).

3-(naphthalen-2-yl)-1H-pyrrolo[3,2-c]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 685 CA 4-15Precipitate2 (yield = 71%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 3.17 min MS (ESI+) m/z = 245.1082 [(M + H)⁺] Mp = <270°C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z = 245.1073; found, 245.1073¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.85 (s, 1H, H₁₃), 9.39 (s, 1H,H₁₂), 8.33 (s, 1H, H₃), 8.28 (d, J = 5.6 Hz, 1H, H₈), 8.05 (d, J = 8.0Hz, 1H, H₁₉₎, 8.02-7.94 (m, 3H, H_(4, 6, 14)), 7.92 (d, J = 8.0 Hz, 1H,H₁₆), 7.53 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H, H₁₈), 7.51-7.45 (m, 2H,H_(9, 17)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 142.94 (C₁₂H-arom.),141.01 (C₈H-arom.), 140.93 (C₁₀-arom.), 134.16 (C₁-arom.), 132.62(C₄-arom.), 131.97 (C₂-arom.), 128.76 (C₆H-arom.), 128.30 (C₁₉H-arom.),127.92 (C₁₆H-arom.), 126.71 (C₁₈H-arom.), 126.21 (C₁₇H-arom.), 125.79(C₅H-arom.), 125.55 (C₁₄H- arom.), 124.55 (C₃H-arom.), 115.92(C₁₅-arom.), 107.71 (C₉H-arom.).

2-phenyl-1H-benzo[d]imidazole

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 686 CA 4-16 F3-14Precipitate (yield = 22%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 2.39 min MS (ESI+) m/z = 195.1040 [(M + H)⁺] Mp = <270°C. HRMS (ESI+): calculated for C₁₃H₁₁N₂, m/z = 195.0917; found, 195.0919¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 12.91 (s, 1H, H₁₃), 8.22-8.17 (m,2H, H_(3, 5)), 7.67 (br s, 1H, H₉), 7.59-7.47 (m, 4H, H_(1, 2, 6, 12)),7.22-7.19 (m, 2H, H_(7, 8)). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) =151.19 (C₁₄-arom.), 143.79 (C₁₀- arom.), 134.98 (C₁₁-arom.), 130.15(C₄-arom.), 129.81 (C₂H-arom.), 128.92 (C_(1, 6)H-arom.), 126.40(C_(3, 5)H-arom.), 122.50 (C₇H-arom.), 121.64 (C₈H-arom.), 118.85(C₉H-arom.), 111.30 (C₁₂H-arom.).

2-naphthalen-3-ol-1H-benzo[d]imidazole

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 687 CA 4-17Precipitate2 (yield = 14%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 3.32 min MS (ESI+) m/z = 261.1080 [(M + H)⁺] Mp = <270°C. HRMS (ESI+): calculated for C₁₇H₁₃N₂O, m/z = 261.1022; found,261.1022 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 13.46 (s, 1H, H₂₀), 13.01(s, 1H, H₁₃), 8.72 (s, 1H, H₃), 7.90 (d, J = 8.2 Hz, 1H, H₁₉), 7.79 (d,J = 8.4 Hz, 1H, H₁₆), 7.74 (br s, 2H,, H_(9, 12)), 7.51 (t, J = 7.5 Hz,1H, H₁₇), 7.43 (s, 1H, H₆), 7.39 (t, J = 7.5 Hz, 1H, H₁₈), 7.34 (br s,2H, H_(7, 8)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 154.60 (C₅-arom.),151.15 (C₁₄- arom.), 141.03 (C₁₀-arom.), 135.16 (C₂-arom.), 133.41(C₁₁-arom.), 128.13 (C₁₉H-arom.), 127.65 (C₁₇H-arom.), 126.99(C₁-arom.), 126.80 (C₃H-arom.), 126.05 (C₁₆H-arom.), 123.77(C₁₈H-arom.), 123.60 (C₇H-arom.), 122.57 (C₈H- arom.), 118.21(C₉H-arom.), 115.21 (C₄-arom.), 111.72 (C₁₂H-arom.), 110.80 (C₆H-arom.).

tert-butyl 3-iodo-7-nitro-1H-indole-1-carboxylate

LabBook Code Intermediate CA 4-18 F4-18 (yield = 90%)

t_(R) (HPLC) = 5.24 min MS (ESI+) m/z = 410.9828 [(M + Na)⁺] ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 8.10 (s, 1H, H₈), 7.99 (dd, J = 7.9, 0.7 Hz,1H, H₂), 7.78 (dd, J = 7.9, 1.0 Hz, 1H, H₆), 7.56 (t, J = 7.9 Hz, 1H,H₁), 1.56 (s, 9H, H_(13,14,15)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =147.76 (C₁₆O), 138.62 (C₃-arom.), 135.66 (C₅-arom.), 134.29 (C₈H-arom.),127.30 (C₆H-arom.), 124.77 (C₄- arom.), 124.25 (C₁H-arom.), 121.63(C₂H-arom.), 86.64 (C₁₂(CH₃)₃), 66.56 (C₉-arom.), 27.76(C_(13,14,15)H₃).

3-((2H-tetrazol-5-yl)methyl)-1H-indole

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 700 CA 4-21 F3-4(yield =66%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 2.80 min MS (ESI+) m/z = 200.0936 [(M + H)⁺] Mp =174-181° C. HRMS (ESI+): calculated for C₁₀H₁₀N₅, m/z = 200.0931; found,200.0929 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.03 (s, 1H, H₉), 7.43(d, J = 8.0 Hz, 1H, H₆), 7.38 (d, J = 8.1 Hz, 1H, H₃), 7.27 (d, J = 2.4Hz, 1H, H₈), 7.09 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H, H₅), 6.98 (ddd, J =7.9, 7.1, 1.0 Hz, 1H, H₄), 4.38 (d, J = 0.6 Hz, 2H, H₁₀). ¹³C NMR (101MHz, DMSO-d₆): δ (ppm) = 156.20 (C₁₁-arom.), 136.70 (C₂- arom.), 126.98(C₈H-arom.), 124.34 (C₁-arom.), 121.75 (C₄H-arom.), 119.11 (C₅H-arom.),118.57 (C₆H-arom.), 112.02 (C₃H-arom.), 108.78 (C₇-arom.), 19.99(C₁₀H₂).

3-(2H-tetrazol-5-yl)-1H-indole

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 701 CA 4-22 F9-16(yield = 33%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 2.86 min MS (ESI+) m/z = 186.2227 [(M + H)⁺] Mp =220-224° C. HRMS (ESI+): calculated for C₉H₈N₅, m/z = 186.0774; found,186.0776 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.88 (s, 1H, H₉),8.25-8.22 (m, 1H, H₆), 8.11 (d, J = 2.9 Hz, 1H, H₁₁), 7.57-7.53 (m, 1H,H₃), 7.28-7.20 (m, 2H, H_(4,5)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =151.72 (C₁₀-arom.), 136.86 (C₂H-arom.), 127.53 (C₈H-arom.), 124.91(C₁-arom.), 123.08 (C₄H-arom.), 121.27 (C₅H-arom.), 120.77 (C₆H-arom.),112.73 (C₃H-arom.), 99.91 (C₇-arom.).

tert-butyl 3-iodo-7-methyl-1H-indole-1-carboxylate

LabBook Code Intermediate CA 4-23 P1-3 (yield = 81%)

t_(R) (HPLC) = 5.78 min MS (ESI+) m/z = ¹H NMR (400 MHz, DMSO-d₆): δ(ppm) = 7.88 (s, 1H, H₈), 7.30-7.19 (m, 3H, H_(1,2,6)), 2.54 (s, 3H,H₁₁), 1.61 (s, 9H, H_(14,15,16)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =148.55 (C₁₇O), 134.13 (C₄-arom.), 133.33 (C₅-arom.), 132.74 (C₈H-arom.),128.83 (C₂H-arom.), 125.22 (C₃- arom.), 124.29 (C₁H-arom.), 119.45(C₆H-arom.), 84.70 (C₁₃(CH₃)₃), 66.84 (C₉-arom.), 27.90(C_(14,15,16)H₃), 21.68 (C₁₁H₃).

tert-butyl 3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

LabBook Code Intermediate CA 4-24 F1-6 (yield = 77%)

t_(R) (HPLC) = 4.59 min MS (ESI+) m/z = 345.0111 [(M + H)⁺] ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 8.56 (dd, J = 4.7, 1.4 Hz, 1H, H₁), 8.32 (dd, J= 8.3, 1.3 Hz, 1H, H₃), 8.19 (s, 1H, H₈), 7.43 (dd, J = 8.3, 4.7 Hz, 1H,H₂), 1.64 (s, 9H, H_(13,14,15)). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =148.26 (C₁₆O), 147.90 (C₄-arom.), 146.39 (C₁H-arom.), 133.51(C₈H-arom.), 128.04 (C₅-arom.), 122.61 (C₃H-arom.), 120.60 (C₂H-arom.),85.59 (C₁₂(CH₃)₃), 69.42 (C₉-arom.), 28.05 (C_(13,14,15)H₃).

3-(naphthalen-2-yl)-7-nitro-1H-indole (Procedure 10)

LabBook Code VPC Number CA 4-27 F20-51 Precipitate3 (yield = IC₅₀ (eGFP)= 0.2 13 702 56%) IC₅₀ (PSA) = 0.14

t_(R) (HPLC) = 4.40 min MS (ESI+) m/z = 289.0915 [(M + H)⁺] Mp =166-171° C. HRMS (ESI+): calculated for C₁₈H₁₃N₂O₂, m/z = 289.0972;found, 289.0975 ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 10.13 (s, 1H, H₁₃),8.38 (d, J = 7.8 Hz, 1H, H₁₂), 8.28 (d, J = 8.1 Hz, 1H, H₈), 8.11 (s,1H, H₃), 7.99 (d, J = 8.4 Hz, 1H, H₆), 7.95-7.90 (m, 2H, H_(16,19)),7.78 (dd, J = 8.5, 1.8 Hz, 1H, H₅), 7.67 (d, J = 2.4 Hz, 1H, H₁₄),7.59-7.50 (m, 2H, H_(17,18)), 7.35 (t, J = 8.0 Hz, 1H, H₇). ¹³C NMR (101MHz, CDCl₃): δ (ppm) = 133.82 (C₄-arom.), 133.21 (C₉- arom.), 132.41(C₂-arom.), 131.32 (C₁-arom.), 130.08 (C₁₀-arom.), 129.92 (C₁₁-arom.),128.67 (C₆H-arom.), 128.16 (C₁₂H-arom.), 127.83 (C₁₉H-arom.), 127.78(C₁₆H-arom.), 126.48 (C₅H-arom.), 126.42 (C₁₈H-arom.), 126.14(C₃H-arom.), 125.86 (C₁₇H-arom.), 124.23 (C₁₄H-arom.), 119.88(C₁₅-arom.), 119.81 (C₇H-arom.), 119.77 (C₈H-arom.).

3-(naphthalen-2-yl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

LabBook Code VPC Number CA 4-28 Precipitate (yield = IC₅₀ (eGFP) = 0.113 703 84%) IC₅₀ (PSA) = 0.097

t_(R) (HPLC) = 4.28 min MS (ESI+) m/z = 245.1068 [(M + H)⁺] Mp =221-224° C. HRMS (ESI+): calculated for C₁₇H₁₃N₂, m/z = 245.1073; found,245.1068 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.66 (s, 1H, H₁₄), 8.97(d, J = 0.8 Hz, 1H, H₃), 8.53 (dd, J = 4.6, 1.5 Hz, 1H, H₇), 8.35 (dd, J= 8.6, 1.7 Hz, 1H, H₅), 8.33 (d, J = 2.9 Hz, 1H, H₁₄), 7.95-7.90 (m, 2H,H_(6,19)), 7.89-7.84 (m, 2H, H_(9,16)), 7.50 (ddd, J = 8.2, 6.9, 1.4 Hz,1H, H₁₈), 7.44 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H, H₁₇), 7.22 (dd, J = 8.2,4.6 Hz, 1H, H₈). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 144.11(C₁₁-arom.), 143.30 (C₇H-arom.), 134.01 (C₁-arom.), 132.82 (C₄-arom.),131.77 (C₂-arom.), 130.16 (C₁₀-arom.), 128.07 (C_(6,16)H-arom.), 128.06(C₁₉H-arom.), 127.67 (C₁₄H-arom.), 126.53 (C₁₈H-arom.), 125.51(C₅H-arom.), 125.34 (C₁₇H-arom.), 123.77 (C₃H- arom.), 119.47(C₉H-arom.), 117.21 (C₈H-arom.), 114.52 (C₁₅-arom.).

7-bromo-3-(naphthalen-2-yl)-1H-indole (Procedure 10)

LabBook Code CA 4-29 P2 F3-7 (yield = 12%)

t_(R) (HPLC) = 5.13 min MS (ESI+) m/z = 323.0095, 325.0076 [(M + H)⁺] ¹HNMR (400 MHz, DMSO-d₆): δ (ppm) = 11.70 (s, 1H, H₁₃), 8.24 (s, 1H, H₃),8.07 (d, J = 8.0 Hz, 1H, H₁₂), 8.00 (d, J = 8.3 Hz, 1H, H₁₉), 7.98 (d, J= 8.6 Hz, 1H, H₆), 7.94-7.89 (m, 3H, H_(5,14,16)), 7.53 (ddd, J = 8.1,6.7, 1.4 Hz, 1H, H₁₈), 7.48 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H, H₁₇), 7.44(d, J = 7.4 Hz, 1H, H₈), 7.12 (t, J = 7.8 Hz, 1H, H₇). ¹³C NMR → n.d.

3-(naphthalen-2-yl)-1H-indol-7-amine

LabBook Code CA 4-34 F6-10 (yield = 28%)

t_(R) (HPLC) = 4.04 min MS (ESI+) m/z = 259.1295 [(M + H)⁺] ¹H NMR (400MHz, CDCl₃) δ (ppm) = 8.22 (s, 1H, H₁₃), 8.18 (s, 1H, H₇), 7.96-7.88 (m,3H, H_(3,6,10)), 7.85 (dd, J = 8.5, 1.7 Hz, 1H, H₉), 7.62 (d, J = 7.9Hz, 1H, H₁₉), 7.57-7.49 (m, 2H, H_(1,2)), 7.36 (s, 1H, H₁₂), 7.21 (t, J= 7.8 Hz, 1H, H₁₈), 6.69 (d, J = 7.5 Hz, 1H, H₁₇). ¹³C NMR → n.d.

tert-butyl 7-methyl-3-((trimethylsilyl)ethynyl)-1H-indole-1-carboxylate

LabBook Code Intermediate CA 4-35 F5-7 (yield = Quant %)

t_(R) (HPLC) = 5.48 min MS (ESI+) m/z = ¹H NMR (400 MHz, CDCl₃): δ (ppm)= 7.77 (s, 1H, H₈), 7.54 (d, J = 7.6 Hz, 1H, H₆), 7.25 (t, J = 7.5 Hz,1H, H₁), 7.18 (d, J = 7.3 Hz, 1H, H₂), 2.67 (s, 3H), 1.66 (s, 9H), 0.33(s, 9H). ¹³C NMR (101 MHz, CDCl₃): δ (ppm) = 148.78 (C₂₂O), 134.06(C₄-arom.),131.84 (C₅-arom.), 131.67 (C₈H-arom.), 128.58 (C₂H- arom.),125.44 (C₃-arom.), 123.61 (C₁H-arom.), 117.80 (C₆H- arom.), 103.32(C₉-arom.), 97.93 (C₁₂≡), 96.91 (C₁₀≡), 83.94 (C₁₈(CH₃)₃), 28.01(C_(19,20,21)H₃), 22.09 (C₁₁H₃), 0.14 (C_(14,15,16)H₃).

3-([1,1′-biphenyl]-4-yl)-7-methyl-1H-indole (Procedure 10)

LabBook Code VPC Number CA 4-38 Precipitate (yield = IC₅₀ (eGFP) = 3.81513 733 25%) IC₅₀ (PSA) = 0.919

t_(R) (HPLC) = 4.50 min MS (ESI−) m/z = 282.1207 [(M + H)⁻] Mp =199-202° C. HRMS (ESI−): calculated for C₂₁H₁₆N, m/z = 282.1288; found,282.1286 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.38 (s, 1H, H₁₃),7.84-7.79 (m, 2H, H_(3,5)), 7.78-7.70 (m, 6H, H_(1,6,12,14,18,22)),7.52-.46 (m, 2H, H_(19,21)), 7.40-7.34 (m, 1H, H₂₀), 7.04 (t, J = 7.2Hz, 1H, H₇), 6.98 (d, J = 7.0 Hz, 1H, H₈), 2.52 (s, 3H, H₁₇). ¹³C NMR(101 MHz, DMSO-d₆): δ (ppm) = 140.51 (C₁₆-arom.), 137.29 (C₂-arom.),136.90 (C₁₀-arom.), 135.75 (C₄-arom.), 129.40 (C_(19,21)H- arom.),127.57 (C₂₀H-arom.), 127.43 (C_(1,6)H-arom.), 127.33 (C_(3,5)H-arom.),126.79 (C_(18,22)H-arom.), 125.14 (C₁₁-arom.), 123.85 (C₁₄H-arom.),122.44 (C₈H-arom.), 121.62 (C₉-arom.), 120.37 (C₇H-arom.), 117.16(C₁₂H-arom.), 116.06 (C₁₅-arom.), 17.31 (C₁₇H₃).

3-([1,1′-biphenyl]-4-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

LabBook Code VPC Number CA 4-39 Precipitate3 (yield = IC₅₀ (eGFP = 4.0813 715 51%) IC₅₀ (PSA) = 0.35

t_(R) (HPLC) = 4.23 min MS (ESI−) m/z = 271.1232 [(M + H)⁺] Mp = <270°C. HRMS (ESI+): calculated for C₁₉H₁₅N₂, m/z = 271.1230; found, 271.1232¹H NMR (500 MHz, DMSO-d₆): δ (ppm) = 11.97 (s, 1H, H₁₃), 8.35 (d, J =7.9 Hz, 1H, H₁₂), 8.30 (dd, J = 4.6, 1.4 Hz, 1H, H₈), 7.96 (d, J = 2.6Hz, 1H, H₁₄). 7.84 (d, J = 8.3 Hz, 2H, H_(3,5)), 7.79-7.71 (m, 4H,H_(1,6,17,21)), 7.49 (t, J = 7.7 Hz, 2H, H_(20,18)), 7.38 (t, J = 7.4Hz, 1H, H₁₉), 7.19 (dd, J = 7.9, 4.6 Hz, 1H, H₇). ¹³C NMR (126 MHz,DMSO-d₆): δ (ppm) = 149.60 (C₁₀-arom.), 143.42 (C₈- arom.), 140.39(C₁₆-arom.), 137.73 (C₂-arom.), 134.78 (C₄-arom.), 129.43(C_(18,20)H-arom.), 128.02 (C₁₂H-arom.), 127.68 (C₁₉H-arom.), 127.55(C_(1,6)H- arom.), 127.11 (C_(3,5)H-arom.), 126.84 (C_(17,21)H-arom.),124.41 (C₁₄H-arom.), 117.74 (C₁₁H-arom.), 116.57 (C₇H-arom.), 114.24(C₁₅-arom.).

3-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

LabBook Code VPC Number CA 4-40 Precipitate (yield = IC₅₀ (eGFP) = 0.06713 716 37%) IC₅₀ (PSA) = 0.058

t_(R) (HPLC) = 3.96 min MS (ESI−) m/z = 273.0029, 275.0010 [(M + H)⁺] Mp= 262-266° C. HRMS (ESI+): calculated for C₁₃H₁₀BrN₂, m/z = 273.0022,275.0002; found, 273.0024, 275.0005 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) =12.00 (s, 1H, H₁₃), 8.30-8.27 (m, 2H, H_(8,12)), 7.95 (d, J = 2.7 Hz,1H, H₁₄), 7.72-7.68 (m, 2H, H_(1,6)), 7.63-7.59 (m, 2H, H_(3,5)),7.20-7.15 (m, 1H, H₇). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 149.54(C₁₀-arom.), 143.52 (C₈H-arom.), 134.83 (C₄-arom.), 132.14(C_(3,5)H-arom.), 128.60 (C_(1,6)H-arom.), 127.89 (C₁₂H-arom.), 124.70(C₁₄H-arom.), 118.79 (C₂-arom.), 117.47 (C₁₁- arom.), 116.64(C₇H-arom.), 113.46 (C₁₅-arom.).

3-([1,1′-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

LabBook Code VPC Number CA 4-48 Precipitate (yield = IC₅₀ (eGFP) = 11.0113 734 39%) IC₅₀ (PSA) = 4.129

t_(R) (HPLC) = 4.34 min MS (ESI−) m/z = 271.1226 [(M + H)⁺] Mp =182-185° C. HRMS (ESI+): calculated for C₁₉H₁₅N₂, m/z = 271.1230; found,271.1227 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.97 (s, 1H, H₁₃), 8.34(dd, J = 8.0, 1.5 Hz, 1H, H₁₂), 8.30 (dd, J = 4.6, 1.5 Hz, 1H, H₈), 8.01(s, 1H, H₁₄), 7.95 (d, J = 0.7 Hz, 1H, H₃), 7.80-7.75 (m, 2H,H_(17,21)), 7.74-7.71 (m, 1H, H₅), 7.57-7.47 (m, 4H, H_(2,6,18,20)),7.43-7.39 (m, 1H, H₁₉), 7.18 (dd, J = 7.9, 4.7 Hz, 1H, H₇). ¹³C NMR (101MHz, DMSO-d₆): δ (ppm) = 149.56 (C₁₀-arom.), 143.39 (C₈H-arom.), 141.37(C₁-arom.), 140.88 (C₁₆-arom.), 136.18 (C₄-arom.), 129.97 (C₆H-arom.),129.38 (C_(18,20)H-arom.), 127.94 (C_(12,19)H-arom.), 127.37(C_(17,21)H- arom.), 125.87 (C₅H-arom.), 125.07 (C₃H-arom.), 124.62(C_(2,14)H-arom.), 117.79 (C₁₁-arom.), 116.59 (C₇H-arom.), 114.66(C₁₅-arom.).

4-(4-bromothiazol-2-yl)morpholine

LabBook Code CA 4-50 Ap Tmt (yield = Quant Intermediate %)

t_(R) (HPLC) = 3.44 min MS (ESI+) m/z = 248.9720; 250.9700 [(M + H)⁺] ¹HNMR (400 MHz, DMSO-d₆): δ (ppm) = 6.92 (s, 1H, H₂), 3.72-3.67 (m, 4H,H_(8,10)), 3.38-3.34 (m, 4H, H_(7,11)). ¹³C NMR (101 MHz, DMSO-d₆): δ(ppm) = 171.17 (C₄-arom.), 121.03 (C₁-arom.), 105.37 (C₂H-arom.), 65.72(C_(8,10)H₂), 48.08 (C_(7,11)H₂).

3-([1,1′-biphenyl]-4-yl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 3.86 13 735 CA 4-55 Precipitate(yield = 79%) IC₅₀ (PSA) = 1.433

t_(R) (HPLC) = 3.55 min MS (ESI−) m/z = 271.1169 [(M + H)⁺] Mp = 254-259° C. HRMS (ESI+): calculated for C₁₉H₁₅N₂, m/z = 271.1230; found,271.1225 ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 11.62 (s, 1H, H₁₃), 8.48(dd, J = 4.6, 1.5 Hz, 1H, H₇), 8.43-8.39 (m, 2H, H_(3,5)), 8.24 (s, 1H,H₁₄), 7.85 (dd, J = 8.2, 1.5 Hz, 1H, H₉), 7.72 (m, 4H, H_(1,6,17,21)),7.49 (m, 2H, H_(18,20)), 7.39-7.35 (m, 1H, H₁₉), 7.20 (dd, J = 8.2, 4.6Hz, 1H, H₈). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 144.02 (C₁₁-arom.),143.19 (C₇H- arom.), 140.64 (C₁₆-arom.), 137.19 (C₂-arom.), 134.48(C₄-arom.), 130.04 (C₁₀- arom.), 129.36 (C_(18,20)H-arom.), 127.50(C₁₉H-arom.), 127.16 (C₁₄H-arom.), 126.99 (C_(1,6)H-arom.), 126.77(C_(17,21)H-arom.), 126.69 (C_(3,5)H-arom.), 119.42 (C₉H-arom.), 117.09(C₈H-arom.), 114.21 (C₁₅-arom.).

3-(4-bromophenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

LabBook Code VPC Number CA 4-64 Precipitate (yield = 25 IC₅₀ (eGFP) =0.08 13 737 %) IC₅₀ (PSA) = 0.037

t_(R) (HPLC) = 2.84 min MS (ESI−) m/z = 273.0043, 275.0023 [(M + H)⁺] Mp= 213-221° C. HRMS (ESI+): calculated for C₁₃H₁₀BrN₂, m/z = 273.0022,275.0002; found, 273.0015, 274.9995 ¹H NMR (400 mHz, DMSO-d₆): δ (ppm) =11.66 (s, 1H, H₁₃), 8.46 (dd, J = 4.6, 1.5 Hz, 1H, H₇), 8.32-8.27 (m,2H, H_(1,6)), 8.24 (s, 1H, H₁₄), 7.84 (dd, J = 8.2, 1.5 Hz, 1H, H₉),7.61-7.55 (m, 2H, H_(3,5)), 7.19 (dd, J = 8.2, 4.6 Hz, 1H, H₈). ¹³C NMR(101 MHz, DMSO-d₆): δ (ppm) = 143.76 (C₁₁-arom.), 143.27 (C₇H-arom.),134.53 (C₄-arom.), 131.61 (C_(3,5)H-arom.), 130.02 (C₁₀-arom.), 128.10(C_(1,6)H-arom.), 127.44 (C₁₄H-arom.), 119.53 (C₉H-arom.), 118.24(C₂-arom.), 117.19 (C₈H-arom.), 113.32 (C₁₅-arom.).

3-(4-bromophenyl)-7-nitro-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.083 13 738 CA 4-65 Precipitate(yield = 12%) IC₅₀ (PSA) = 0.062

t_(R) (HPLC) = 4.29 min MS (ESI−) m/z = 314.9732, 316.9703 [(M + H)⁻] Mp= 192-196° C. HRMS (ESI−): calculated for C₁₄H₈BrN₂O₂, m/z = 314.9775,316.9755; found, 314.9769, 316.9748 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) =12.21 (s, 1H, H₁₃), 8.34 (dd, J = 7.9, 0.8 Hz, 1H, H₁₂), 8.20 (dd, J =8.0, 0.5 Hz, 1H, H₈), 7.89 (s, 1H, H₁₄), 7.71-7.63 (m, 4H, H_(1,3,5,6)),7.36 (t, J = 8.0 Hz, 1H, H₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) =133.24 (C₄-arom.), 132.90 (C₉- arom.), 131.78 (C_(1,6)H-arom.), 129.25(C_(3,5)H-arom.), 129.11 (C₁₁-arom.), 128.95 (C₁₀-arom.), 127.65(C₁₂H-arom.), 126.89 (C₁₄H-arom.), 119.58 (C₇H- arom.), 119.26(C₂-arom.), 119.13 (C₈H-arom.), 116.42 (C₁₅-arom.).

methyl 3-(4-bromophenyl)-1H-indole-7-carboxylate (Procedure 10)

LabBook Code VPC Number CA 4-74 Precipitate (yield = 36 IC₅₀ (eGFP) =0.62 13 736 %) IC₅₀ (PSA) = 0.68

t_(g) (HPLC) = 4.37 min MS (ESI−) m/z = 327.9978 [(M + H)⁻] Mp =149-155° C. HRMS (ESI−): calculated for C₁₆H₁₁BrNO₂, m/z = 327.9979;found, 327.9978 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.49 (s, 1H, H₁₃),8.16 (d, J = 7.9 Hz, 1H, H₁₂), 7.87 (d, J = 6.8 Hz, 1H, H₈), 7.78 (d, J= 2.6 Hz, 1H, H₁₄), 7.70-7.67 (m, 2H, H_(3,5)), 7.65-7.61 (m, 2H,H_(1,6)), 7.26 (t, J = 7.7 Hz, 1H, H₇), 3.97 (s, 3H, H₇). ¹³C NMR (151MHz, DMSO-d₆): δ (ppm) = 166.39 (C₁₇O), 135.02 (C₁₀-arom.), 134.18(C₄-arom.), 131.67 (C_(1,6)H-arom.), 128.88 (C_(3,5)H-arom.), 126.54(C₁₁-arom.), 125.42 (C₁₄H-arom.), 124.83 (C₁₂H-arom.), 124.30(C₈H-arom.), 119.49 (C₇H-arom.), 118.57 (C₂-arom.), 115.07 (C₁₅-arom.),113.07 (C₉-arom.), 51.94 (C₂₀H₃).

3-phenyl-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.66 13 739 CA 4-75 Precipitate(yield = 54%) IC₅₀ (PSA) = 0.67

t_(R) (HPLC) = 3.40 min MS (ESI+) m/z = 195.0920 [(M + H)⁺] Mp = 92-94°C. HRMS (ESI+): calculated for C₁₃H₁₁N₂, m/z = 195.0917; found, 195.0919¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.90 (s, 1H, H₁₃), 8.30-8.26 (m,2H, H_(8,12)), 7.87 (d, J = 2.6 Hz, 1H, H₁₄), 7.73 (dd, J = 8.2, 1.1 Hz,2H, H_(3.5)), 7.45 (dd, J = 8.0, 7.5 Hz, 2H, H_(1,6)), 7.26 (tdd, J =7.2, 6.0, 1.2 Hz, 1H, H₂), 7.16 (dd, J = 7.9, 4.7 Hz, 1H, H₇). ¹³C NMR(151 MHz, DMSO-d₆): δ (ppm) = 149.06 (C₁₀-arom.), 142.87 (C₈H- arom.),135.05 (C₄-arom.), 128.84 (C_(1,6)H-arom.), 127.43 (C₁₂H-arom.), 126.23(C_(3,5)H-arom.), 125.63 (C₂H-arom.), 123.67 (C₁₄H-arom.), 117.25(C₁₁-arom.), 116.00 (C₇H-arom.), 114.25 (C₁₅-arom.).

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-tert-butylcarboxylate

LabBook Code Intermediate CA 4-76 F2-6 (yield = 68%)

t_(R) (HPLC) = 4.99 min MS (ESI+) m/z = n.d. ¹H NMR (400 MHz, DMSO-d₆):δ (ppm) = 8.11-8.06 (m, 1H, H₃), 7.88 (s, 1H, H₈), 7.87-7.82 (m, 1H,H₆), 7.37-7.32 (m, 1H, H₂), 7.31-7.26 (m, 1H, H₁), 1.64 (s, 9H,H_(21,22,23)), 1.33 (s, 12H, H_(15,16,17,18)). ¹³C NMR (101 MHz,DMSO-d₆): δ (ppm) = 149.11 (C₂₄O), 135.87 (C₄- arom.), 135.33(C₈H-arom.), 133.22 (C₅-arom.), 124.86 (C₂H-arom.), 123.48 (C₁H-arom.),122.66 (C₆H-arom.), 115.06 (C₃H-arom.), 107.92 (C₉-arom.), 84.79(C₂₀(CH₃)₃), 83.74 (C_(12,13)(CH₃)₂), 28.07 (C_(21,22,23)H₃), 25.14(C_(15,16,17,18)H₃).

3-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.12 13 740 CA 4-85 Precipitate(yield = 50%) IC₅₀ (PSA) = 0.12

t_(R) (HPLC) = 3.59 min MS (ESI+) m/z = 213.0830 [(M + H)⁺] Mp =188-192° C. HRMS (ESI+): calculated for C₁₃H₁₀FN₂, m/z = 213.0823;found, 213.0823 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.91 (s, 1H, H₁₃),8.28 (dd, J = 4.6, 1.3 Hz, 1H, H₁₂), 8.26 (dd, J = 8.0, 1.1 Hz, 1H, H₈),7.86 (d, J = 2.6 Hz, 1H, H₁₄), 7.77-7.73 (m, 2H, H_(3.5)), 7.29-7.24 (m,2H, H_(1,6)), 7.16 (dd, J = 7.9, 4.6 Hz, 1H, H₇). ¹³C NMR (151 MHz,DMSO-d₆): δ (ppm) = 160.52 (d, J = 242.3 Hz, C₂F- arom.), 148.96(C₁₀-arom.), 142.92 (C₈H-arom.), 131.49 (d, J = 3.0 Hz, C₄- arom.),127.99 (d, J = 7.8 Hz, C_(3,5)H-arom.), 127.27 (C₁₂H-arom.), 123.66(C₁₄H-arom.), 117.15 (C₁₁-arom.), 116.02 (C₇H-arom.), 115.61 (d, J =21.2 Hz, C_(1,6)H-arom.), 113.28 (C₁₅-arom.).

3-(5-(trifluoromethyl)pyridin-2-yl)-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.29 13 741 CA 4-88 Crystals(yield = 22%) IC₅₀ (PSA) = 0.29

t_(R) (HPLC) = 4.03 min MS (ESI+) m/z = 263.0793 [(M + H)⁺] Mp =154-157° C. HRMS (ESI+) : calculated for C₁₄H₂₁₀F₃N₂, m/z = 263.0791;found, 263.0789 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.77 (s, 1H, H₁₃),8.94-8.92 (m, 1H, H₁), 8.50 (d, J = 7.7 Hz, 1H, H₁₂), 8.32 (d, J = 2.9Hz, 1H, H₁₄), 8.02-8.04 (m, 2H, H_(5,6)), 7.49 (d, J = 7.8 Hz, 1H, H₉),7.23-7.16 (m, 2H, H_(7,8)). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 159.25(d, J = 1.2 Hz, C₄-arom.), 145.86 (q, J = 4.2 Hz, C₁H-arom.), 137.12(C₁₀-arom.), 133.25 (q, J = 3.1 Hz, C₆H-arom.), 128.17 (C₁₄H-arom.),125.13 (C₁₁-arom.), 124.31 (q, J = 271.5 Hz, C₁₆F₃), 122.14 (C₈H-arom.),121.63 (C₁₂H-arom.), 120.55 (C₇H-arom.), 120.30 (q, J = 32.1 Hz,C₂-arom.), 119.02 (C₅-arom.), 114.24 (C₁₅-arom.), 111.99 (C₉H-arom.).

tert-butyl7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

LabBook Code Intermediate CA 4-89 F10-24 (yield = 68%)

t_(R) (HPLC) = 5.20 min MS (ESI+) m/z = n.d. ¹H NMR (400 MHz, DMSO-d₆):δ (ppm) = 7.85 (s, 1H, H₈), 7.71 (d, J = 7.1 Hz, 1H, H₆), 7.19 (t, J =7.5 Hz, 1H, H₁), 7.11 (d, J = 7.1 Hz, 1H, H₂), 2.53 (s, 3H, H₁₉), 1.62(s, 9H, H_(22,23,24)), 1.33 (s, 12H, H_(15,16,17,18)). ¹³C NMR (151 MHz,DMSO-d₆): δ (ppm) = 148.60 (C₂₅O), 137.15 (C₈H- arom.), 134.66(C₄-arom.), 133.93 (C₅-arom.), 127.27 (C₂H-arom.), 124.23 (C₃-arom.),123.28 (C₁H-arom.), 119.88 (C₆H-arom.), 107.29 (C₉-arom.), 84.18(C₂₀(CH₃)₃), 83.18 (C_(12,13)(CH₃)₂), 27.42 (C_(22,23,24)H₃), 24.67(C_(15,16,17,18)H₃, 21.39 (C₁₉H₃).

3-(2-(trifluoromethyl)phenyl)-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 1.01 13 745 CA 4-95 F4-8 (yield =50%) IC₅₀ (PSA) = 0.95

t_(R) (HPLC) = 4.15 min MS (ESI+) m/z = 260.0687 [(M + H)⁺] Mp = 62-67°C. HRMS (ESI−): calculated for C₁₅H₉F₃N, m/z = 260.0693; found, 260.0687¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.39 (s, 1H, H₁₃), 7.85 (d, J =7.9 Hz, 1H, H₁), 7.72 (t, J = 7.4 Hz, 1H, H₆), 7.59 (d, J = 7.5 Hz, 1H,H₅), 7.55 (t, J = 7.5 Hz, 1H, H₂), 7.49 (d, J = 8.1 Hz, 1H, H₉), 7.40(s, 1H, H₁₄), 7.36 (d, J = 7.9 Hz, 1H, H₁₂), 7.16 (t, J = 7.5 Hz, 1H,H₈), 7.04 (t, J = 7.4 Hz, 1H, H₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) =135.73 (C₁₀-arom.), 134.23 (d, J = 1.3 Hz, C₄-arom.), 133.18(C₅H-arom.), 132.04 (C₆H-arom.), 127.71 (q, J = 28.6 Hz, C₃-arom.),127.01 (C₁₁-arom.), 126.89 (C₂H-arom.), 126.26 (q, J = 5.4 Hz,C₁H-arom.), 124.40 (d, J = 2.9 Hz, C₁₄H-arom.), 124.39 (q, J = 273.6 Hz,C₁₆F₃), 121.46 (C₈H-arom.), 119.42 (C₇H-arom.), 118.32 (C₁₂H-arom.),112.44 (C₁₅-arom.), 111.70 (C₉H-arom.).

2,3,4-trifluoro-6-iodoaniline

LabBook Code Intermediate CA 4-100 F6-11 (yield = 36%)

t_(R) (HPLC) = 3.78 min MS (ESI+) m/z = 273.9338 [(M + H)⁺] ¹H NMR( 600MHz, CDCl₃): δ (ppm) = 7.33 (ddd, J = 9.3, 7.6, 2.5 Hz, 1H, H₆), 4.07(s, 2H, H₇). ¹³C NMR (151 MHz, CDCl₃): δ (ppm) = 143.20 (ddd, J = 244.0,10.8, 2.8 Hz, C₃-arom.), 139.98 (ddd, J = 250.5, 161.1, 13.7 Hz,C₂-arom.), 138.48 (ddd, J = 247.1, 12.6, 3.3 Hz, C₁-arom.), 133-43 (dd,J = 11.2 2.4 Hz, C₄-arom.), 119.96 (dd, J = 20.1, 3.9 Hz, C₆H-arom.),73.21 (ddd, J = 8.2, 4.5, 2.1 Hz, C₅-arom.).

2-(5,6,7-trifluoro-1H-indol-3-yl)quinoline

LabBook Code CA 4-101 F4-6 (yield = 13%)

t_(R) (HPLC) = 4.32 min MS (ESI+) m/z = 299.0820 [(M + H)⁺] HRMS (ESI+):calculated for C₁₇H₁₀F₃N₂, m/z = 299.0791; found, 299.0791 ¹H NMR (600MHz, CDCl₃): δ (ppm) = 9.99 (s, 1H, H₁₅), 8.21 (d, J = 8.4 Hz, 1H, H₁₀),8.12 (d, J = 8.1 Hz, 1H, H₃), 7.87 (d, J = 8.4 Hz, 1H, H₉), 7.84 (d, J =8.4 Hz, 1H, H₆), 7.77 (t, J = 7.5 Hz, 1H, H₂), 7.57 (t, J = 7.3 Hz, 1H,H₁), 7.23 (ddd, J = 9.7, 6.5, 1.6 Hz, 1H, H₁₉), 7.12 (s, 1H, H₁₄). ¹³CNMR (151 MHz, CDCl₃): δ (ppm) = 148.30 (C₈-arom.), 147.32 (C₄-arom.),146.70 (dd, J = 240.3, 12.2 Hz, C₁₆-arom.), 138.72 (C₁₃-arom.), 137.53(ddd, J = 249.3, 13.6, 4.5 Hz, C₁₇-arom.), 136.93 (ddd, J = 244.8, 17.1,11.3 Hz, C₁₆- arom.), 136.35 (C₁₀-arom.), 129.70 (C₂H-arom.), 128.58(C₃H-arom.), 127.22 (C₆H-arom.), 127.06 (C₅-arom.), 126.14 (C₁H-arom.),124.01 (dd, J = 6.9, 5.5 Hz, C₁₂-arom.), 121.44 (dd, J = 7.7, 2.9 Hz,C₁₁-arom.), 117.52 (C₉H-arom.), 101.92 (m, C_(14,19)H-arom.).

7-(7-methyl-1H-indol-3-yl)quinoline (Procedure 10)

LabBook Code VPC Number CA 4-102 Precipitate (yield = 32 IC₅₀ (eGFP) =0.76 13 744 %) IC₅₀ (PSA) = 0.75

t_(R) (HPLC) = 2.94 min MS (ESI+) m/z = 259.1272 [(M + H)⁺] Mp =199-201° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found,259.1228 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.54 (s, 1H, H₁₃), 8.89(dd, J = 4.2, 1.7 Hz, 1H, H₁₉), 8.34 (dd, J = 8.2, 0.9 Hz, 1H, H₁₇),8.30 (s, 1H, H₃), 8.04-8.00 (m, 2H, H_(5,6)), 7.98 (d, J = 2.4 Hz, 1H,H₁₄), 7.87 (d, J = 8.0 Hz, 1H, H₁₂), 7.47 (dd, J = 8.2, 4.2 Hz, 1H,H₁₈), 7.10 (t, J = 7.5 Hz, 1H, H₈), 7.02 (d, J = 7.0 Hz, 1H, H₈), 2.54(s, 3H, H₁₆). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 150.65 (C₁₉H-arom.),148.56 (C₁- arom.), 137.35 (C₄-arom.), 136.61 (C₁₀-arom.), 135.55(C₁₇H-arom.), 128.24 (C₆H-arom.), 126.41 (C₅H-arom.), 125.92 (C₂-arom.),124.71 (C₁₄H-arom.), 124.62 (C₁₁-arom.), 124.05 (C₃H-arom.), 122.23(C₈H-arom.), 121.36 (C₉- arom.), 120.40 (C₇H-arom.), 120.28(C₁₈H-arom.), 116.64 (C₁₂H-arom.), 115.27 (C₁₅-arom.), 16.83 (C₁₆H₃).

tert-butyl 3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

LabBook Code Intermediate CA 4-104 F1-21 (yield = 83%)

t_(R) (HPLC) = 4.07 min MS (ESI+) m/z = 345.0106 [(M + H)⁺] ¹H NMR (400MHz, DMSO-d₆): δ (ppm) = 8.56 (dd, J = 4.7, 1.4 Hz, 1H, H₁), 8.32 (dd, J= 8.3, 1.3 Hz, 1H, H₃), 8.19 (s, 1H, H₈), 7.43 (dd, J = 8.3, 4.7 Hz, 1,H₂), 1.64 (s, 9H, H_(13,14,15)). ¹³C NMR = n.d.

3-(4-(trifluoromethyl)phenyl)-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.38 13 743 CA 4-105 F8-16 (yield= 51%) IC₅₀ = 0.39

t_(R) (HPLC) = 4.34 min MS (ESI+) m/z = 262.0850 [(M + H)⁺] Mp =126-129° C. HRMS (ESI+): calculated for C₁₅H₁₁F₃N, m/z = 262.0838;found, 262.0850 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.59 (s, 1H, H₁₃),7.94 (d, J = 8.2 Hz, 3H, H_(3.5,12)), 7.90 (d, J = 2.6 Hz, 1H, H₁₄),7.76 (d, J = 8.2 Hz, 2H, H_(1,6)), 7.50 (d, J = 8.0 Hz, 1H, H₉),7.22-7.18 (m, 1H, H₈), 7.17-7.13 (m, 1H, H₇). ¹³C NMR (151 MHz,DMSO-d₆): δ (ppm) = 140.18 (d, J = 0.8 Hz, C₄-arom.), 137.04(C₁₀-arom.), 126.48 (C_(3,5)H-arom.), 125.58 (q, J = 3.7 Hz,C_(1,6)H-arom.), 125.25 (d, J = 31.7 Hz, C₂-arom.), 125.00 (C₁₄H-arom.),124.66 (C₁₁H-arom.), 124.62 (q, J = 271.5 Hz, C₁₆F₃), 121.76(C₈H-arom.), 120.11 (C₇H-arom.), 118.92 (C₁₂H-arom.), 114.12(C₁₅-arom.), 112.19 (C₉H-arom.).

1-methyl-5-(naphthalen-2-yl)-1H-indole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 2.0 13 756 CA 4-108 Precipitate(yield = 45%) IC₅₀ (PSA) = 1.49

t_(R) (HPLC) = 4.56 min MS (ESI+) m/z = 258.1260 [(M + H)⁺] Mp =200-204° C. HRMS (ESI+): calculated for C₁₉H₁₆N, m/z = 258.1277; found,258.1276 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 8.21 (d, J = 0.7 Hz, 1H,H₇), 8.00- 7.97 (m, 3H, H_(6,10,16)), 7.93 (d, J = 8.0 Hz, 1H, H₃), 7.91(dd, J = 8.5, 1.7 Hz, 1H, H₉), 7.64 (dd, J = 8.5, 1.6 Hz, 1H, H₁₄), 7.57(d, J = 8.5 Hz, 1H, H₁₃), 7.54 (t, J = 7.3 Hz, 1H, H₁), 7.49 (t, J = 7.3Hz, 1H, H₂), 7.39 (d, J = 3.0 Hz, 1H, H₁₈), 6.53 (d, J = 3.0 Hz, 1H,H₁₉), 3.85 (s, 3H, H₂₀). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 139.02(C₈-arom.), 136.09 (C₁₁- arom.), 133.52 (C₅-arom.), 131.70 (C₄-arom.),131.12 (C₁₅-arom.), 130.43 (C₁₈H- arom.), 128.68 (C₁₂-arom.), 128.20(C₁₀H-arom.), 127.95 (C₆H-arom.), 127.41 (C₃H-arom.), 126.19(C₁H-arom.), 125.62 (C₂H-arom.), 125.50 (C₉H-arom.), 124.60 (C₇H-arom.),120.61 (C₁₄H-arom.), 118.75 (C₁₆H-arom.), 110.20 (C₁₃H- arom.), 100.86(C₁₉H-arom.), 32.58 (C₂₀H₃).

3-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (EGFP) = 13 CA 4-109 Precipitate (yield =69%) IC₅₀ (PSA) =

t_(R) (HPLC) = 2.89 min MS (ESI+) m/z = 263.0792 [(M + H)⁺] Mp =223-226° C. HRMS (ESI+): calculated for C₁₄H₁₀F₃N₂, m/z = 263.0791;found, 263.0790 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.78 (s, 1H, H₁₁),8.55 (d, J = 8.2 Hz, 2H, H_(3,5)), 8.49 (dd, J = 4.5, 1.3 Hz, 1H, H₁₃),8.36 (s, 1H, H₇), 7.87 (dd, J = 8.2, 1.4 Hz, 1H, H₁₅), 7.75 (d, J = 8.3Hz, 2H, H_(2,6)), 7.22 (dd, J = 8.2, 4.5 Hz, 1H, H₁₄). ¹³C NMR (101 MHz,DMSO-d₆): δ (ppm) = 143.41 (C₉-arom.), 143.07 (C₁₃H- arom.), 139.02 (d,J = 0.9 Hz, C₄-arom.), 129.64 (C₁₀-arom.), 128.07 (C₇H- arom.), 125.77(C_(3,5)H-arom.), 125.16 (q, J = 3.7 Hz, C_(2,6)H-arom.), 125.14 (q, J =31.6 Hz, C₁-arom.), 124.67 (q, J = 271.4 Hz, C₁₆F₃), 119.23(C₁₅H-arom.), 116.93 (C₁₄H-arom.), 112.60 (C₈-arom.).

3-(2-bromophenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

LabBook Code CA 4-110 Precipitate2 (yield = 37%)

t_(R) (HPLC) = 2.61 min MS (ESI+) m/z = 273.0018, 274.9998 [(M + H)⁺]HRMS (ESI+): calculated for C₁₃H₁₀BrN₂, m/z = 2273.0022, 275.0002;found, 273.0018, 274.9998 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.61 (s,1H, H₁₁), 8.37 (d, J = 4.4 Hz, 1H, H₁₃), 7.99 (s, 1H, H₇), 7.90 (d, J =7.7 Hz, 1H, H₅), 7.85 (d, J = 8.1 Hz, 1H, H₁₅), 7.74 (d, J = 7.9 Hz, 1H,H₂), 7.45 (t, J = 7.5 Hz, 1H, H₆), 7.24 (t, J = 7.6 Hz, 1H, H₁), 7.18(dd, J = 8.1, 4.5 Hz, 1H, H₁₄). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) =143.75 (C₉-arom.), 142.71 (C₁₃H- arom.), 134.57 (C₄-arom.), 132.93(C₃H-arom.), 132.70 (C₅H-arom.), 128.75 (C₇H-arom.), 128.29 (C₁₀-arom.),127.86 (C₁H-arom.), 127.21 (C₆H-arom.), 122.57 (C₃-arom.), 118.89(C₁₅H-arom.), 116.70 (C₁₄H-arom.), 113.74 (C₈-arom.).

6-(7-methyl-1H-indol-3-yl)benzo[d]thiazole (Procedure 10)

VPC Number LabBook Code IC₅₀ = (eGFP) = Inactive 13 757 CA 4-114 F9-15Precipitate (yield = 27%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 4.02 min MS (ESI+) m/z = 265.0787 [(M + H)⁺] Mp =183-185° C. HRMS (ESI+): calculated for C₁₆H₁₃N₂S, m/z = 265.0794;found, 265.0793 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.42 (s, 1H, H₁₄),9.32 (s, 1H, H₈), 8.48 (d, J = 0.8 Hz, 1H, H₆), 8.12 (d, J = 8.5 Hz, 1H,H₃), 7.90 (dd, J = 8.5, 1.6 Hz, 1H, H₄), 7.84-7.80 (m, 2H, H_(13,18)),7.05 (t, J = 7.5 Hz, 1H, H₁₇), 6.99 (d, J = 7.0 Hz, 1H, H₁₆), 2.52 (s,3H, H₁₉). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 154.81 (C₈H-arom.),150.95 (C₁- arom.), 136.43 (C₁₀-arom.), 134.50 (C₂-arom.), 133.67(C₅-arom.), 125.37 (C₄H- arom.), 124.63 (C₁₁-arom.), 123.87(C₁₃H-arom.), 123.01 (C₃H-arom.), 122.07 (C₁₆H-arom.), 121.15(C₁₅-arom.), 119.98 (C₁₇H-arom.), 119.15 (C₆H-arom.), 116.70(C₁₈H-arom.), 115.44 (C₁₂-arom.), 16.81 (C₁₉H₃).

2-(quinolin-5-yl)thiazole

LabBook Code CA 4-116 F14-17 (yield = 36%)

t_(R) (HPLC) = 2.95 min MS (ESI+) m/z = 213.0468 [(M + H)⁺] ¹H NMR (600MHz, DMSO-d₆): δ (ppm) = 9.31 (d, J = 8.7 Hz, 1H, H₆), 9.00 (dd, J =4.0, 1.6 Hz, 1H, H₄), 8.18 (d, J = 8.4 Hz, 1H, H₁₀), 8.13 (d, J = 3.3Hz, 1H, H₁₂), 8.05 (d, J = 7.2 Hz, 1H, H₈), 7.98 (d, J = 3.3 Hz, 1H,H₁₁), 7.89 (dd, J = 8.3, 7.4 Hz, 1H, H₉), 7.67 (dd, J = 8.7, 4.1 Hz, 1H,H₅). ¹³C NMR (101 MHz, DMSO-d₆): δ (ppm) = 165.68 (C₁₄-arom.), 150.97(C₄H-arom.), 148.04 (C₂-arom.), 143.95 (C₁₂H-arom.), 134.04 (C₆H-arom.),131.25 (C₁₀H-arom.), 130.17 (C₇-arom.), 129.09 (C₉H- arom.), 128.68(C₈H-arom.), 124.92 (C₁-arom.), 122.51 (C₅H-arom.), 121.55 (C₁₁H-arom.).

5-(7-methyl-1H-indol-3-yl)benzo[d]thiazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = Inactive 13 758 CA 4-118 F18-25(yield = 68%) IC₅₀ (PSA) = Inactive

t_(R) (HPLC) = 3.93 min MS (ESI+) m/z = 265.0790 [(M + H)⁺] Mp =133-136° C. HRMS (ESI+): calculated for C₁₆H₁₃N₂S, m/z = 265.0794;found, 265.0790 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.43 (s, 1H, H₁₅),9.41 (s, 1H, H₈), 8.39 (d, J = 1.1 Hz, 1H, H₆), 8.20 (d, J = 8.3 Hz, 1H,H₃), 7.87 (dd, J = 8.4, 1.5 Hz, 1H, H₄), 7.86 (d, J = 2.6 Hz, 1H, H₁₃),7.79 (d, J = 8.0 Hz, 1H, H₁₈), 7.06 (t, J = 7.5 Hz, 1H, H₁₇), 6.99 (d, J= 7.0 Hz, 1H, H₁₆), 2.54 (s, 3H, H₁₉). ¹³C NMR (151 MHz, DMSO-d₆): δ(ppm) = 156.22 (C₈H-arom.), 153.99 (C₂- arom.), 136.44 (C₁₀-arom.),134.47 (C₅-arom.), 130.24 (C₁-arom.), 124.84 (C₄H- arom.), 124.70(C₁₁-arom.), 123.76 (C₁₃H-arom.), 122.52 (C₃H-arom.), 122.05(C₁₆H-arom.), 121.21 (C₁₅-arom.), 120.04 (C₆H-arom.), 120.01(C₁₇H-arom.), 116.45 (C₁₈H-arom.), 115.56 (C₁₂-arom.), 16.83 (C₁₉H₃).

5-(7-methyl-1H-indol-3-yl)benzo[d]oxazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.3 13 759 CA 4-119 Precipitate(yield = 26%) IC₅₀ (PSA) = 0.27

t_(R) (HPLC) = 3.87 min MS (ESI+) m/z = 249.1041 [(M + H)⁺] Mp =171-172° C. HRMS (ESI+): calculated for C₁₆H₁₃N₂O, m/z = 249.1022;found, 249.1016 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.35 (s, 1H, H₁₄),8.75 (s, 1H, H₈), 8.03 (d, J = 1.3 Hz, 1H, H₆), 7.82 (d, J = 8.4 Hz, 1H,H₃), 7.77 (dd, J = 8.4, 1.6 Hz, 1H, H₄), 7.75 (d, J = 2.6 Hz, 1H, H₁₃),7.72 (d, J = 8.0 Hz, 1H, H₁₈), 7.03 (t, J = 7.5 Hz, 1H, H₁₇), 6.98 (d, J= 7.0 Hz, 1H, H₁₆), 2.52 (s, 3H, H₁₉). ¹³C NMR (151 MHz, DMSO-d₆): δ(ppm) = 154.42 (C₈H-arom.), 147.60 (C₁- arom.), 140.40 (C₂-arom.),136.31 (C₁₀-arom.), 132.98 (C₅-arom.), 124.75 (C₄H- arom.), 124.70(C₁₁-arom.), 123.40 (C₁₃H-arom.), 121.95 (C₁₆H-arom.), 121.11(C₁₅-arom.), 119.88 (C₁₇H-arom.), 117.38 (C₆H-arom.), 116.32(C₁₈H-arom.), 115.79 (C₁₂-arom.), 111.18 (C₃H-arom.), 16.81 (C₁₉H₃).

2-(7-methyl-1H-indol-3-yl)benzo[d]thiazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.1 13 760 CA 4-120 F12-18Precipitate (yield = 30%) IC₅₀ (PSA) = 0.52

t_(R) (HPLC) = 4.02 min MS (ESI+) m/z = 265.0788 [(M + H)⁺] Mp =179-182° C. HRMS (ESI+): calculated for C₁₆H₁₃N₂S, m/z = 265.0794;found, 265.0790 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm): = 11.95 (s, 1H, H₅),8.25 (d, J = 2.9 Hz, 1H, H₄), 8.22 (d, J = 7.9 Hz, 1H, H₉), 8.06 (d, J =7.9 Hz, 1H, H₁₃), 7.97 (d, J = 8.1 Hz, 1H, H₁₆), 7.49 (t, J = 7.6 Hz,1H, H₁₅), 7.37 (t, J = 7.6 Hz, 1H, H₁₄), 7.17 (t, J = 7.5 Hz, 1H, H₈),7.07 (d, J = 7.1 Hz, 1H, H₇), 2.54 (s, 3H, H₁₀). ¹³C NMR (151 MHz,DMSO-d₆): δ (ppm) = 162.90 (C₁₈-arom.), 153.68 (C₁₂- arom.), 136.26(C₁-arom.), 133.03 (C₁₁-arom.), 128.52 (C₄H-arom.), 126.09 (C₁₅H-arom.),124.32 (C₂-arom.), 124.17 (C₁₄H-arom.), 123.25 (C₇-arom.), 121.71(C₁₃H-arom.), 121.63 (C₆-arom.), 121.53 (C₁₆H-arom.), 121.30 (C₈H-arom.), 118.22 (C₉H-arom.), 110.81 (C₃-arom.), 16.74 (C₁₀H₃).

3-(3-bromophenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

LabBook Code CA 4-124 Precipitate (yield = 30%)

t_(R) (HPLC) = 2.71 min MS (ESI+) m/z = 273.0006, 274.9986 [(M + H)⁺]HRMS (ESI+): calculated for C₁₃H₁₀BrN₂, m/z = 273.0022, 275.0002; found,273.0023, 275.0003 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.69 (s, 1H),8.65 (s, 1H), 8.49 (d, J = 3.5 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.28-8.25 (m, 1H), 7.85 (dd, J = 8.2, 1.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.20(dd, J = 8.1, 4.6 Hz, 1H). ¹³C NMR = n.d.

4-bromo-2-(7-methyl-1H-indol-3-yl)thiazole (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 0.045 13766 CA 4-125 F7-11 (yield= 43%) IC₅₀ (PSA) = 0.02

t_(R) (HPLC) = 4.00 min MS (ESI+) m/z = 292.9743, 294.9724 [(M + H)⁺] Mp= 127-130° C. HRMS (ESI+): calculated for C₁₂H₁₀BrN₂S, m/z = 292.9743,294.9722; found, 292.9743, 294.9723 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) =11.86 (s, 1H, H₅), 8.16 (s, 1H, H₄), 7.93 (d, J = 7.7 Hz, 1H, H₉), 7.62(s, 1H, H₁₄), 7.13 (t, J = 7.3 Hz, 1H, H₈), 7.04 (d, J = 6.6 Hz, 1H,H₇), 2.52 (s, 3H, H₁₀). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 164.43(C₁₁-arom.), 136.06 (C₁- arom.), 126.82 (C₄H-arom.), 123.71 (C₁₃-arom.),123.69 (C₂-arom.), 123.09 (C₇H-arom.), 121.67 (C₆H-arom.), 121.19(C₈H-arom.), 117.45 (C₉H-arom.), 113.69 (C₁₄H-arom.), 110.13 (C₃-arom.),16.71 (C₁₀H₃).

tert-butyl 6-fluoro-3-iodo-1H-indole-1-carboxylate

LabBook Code CA 4-126 F1-6 Intermediate (yield = 95%)

t_(R) (HPLC) = 4.80 min MS (ESI+) m/z = n.d. ¹H NMR (600 MHz, DMSO-d₆):δ (ppm) = 7.90 (s, 1H, H₈), 7.82 (dd, J = 10.2, 2.0 Hz, 1H, H₃), 7.40(dd, J = 8.7, 5.3 Hz, 1H, H₆), 7.24 (td, J = 9.1, 2.4 Hz, 1H, H₁), 1.64(s, 9H, H_(14,15,16)). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm): = 160.69 (d,J = 239.6 Hz, C₂-arom.), 147.88 (C₁₇O), 134.17 (d, J = 13.2 Hz,C₄-arom.), 130.75 (d, J = 3.8 Hz, C₈H-arom.), 128.47 (C₅-arom.), 122.61(d, J = 10.3 Hz, C₆H- arom.), 111.66 (d, J = 24.4 Hz, C₁H-arom.), 101.61(d, J = 28.9 Hz, C₃H-arom.), 84.90 (C₁₃), 66.05 (C₉-arom.), 27.55 (sC_(14,15,16)H₃).

3-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]pyridine (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = 13 CA 4-127 Precipitate (yield =89%) IC₅₀ (PSA) =

t_(R) (HPLC) = 2.54 min MS (ESI+) m/z = 225.1037 [(M + H)⁺] Mp =202-206° C. HRMS (ESI+): calculated for C₁₄H₁₃N₂O, m/z = 225.1022;found, 2251027 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.42 (s, 1H, H₁₁),8.43 (dd, J = 4.5, 1.5 Hz, 1H, H₁₃), 8.22-8.18 (m, 2H, H_(2,6)), 8.04(d, J = 2.8 Hz, 1H, H₇), 7.80 (dd, J = 8.2, 1.5 Hz, 1H, H₁₅), 7.16 (dd,J = 8.1, 4.5 Hz, 1H, H₁₄), 7.01-6.96 (m, 2H, H_(3,5)), 3.79 (s, 3H,H₁₇). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) = 157.12 (C₁-arom.), 143.36(C₉- arom.), 142.39 (C₁₃H-arom.), 129.37 (C₁₀-arom.), 127.28 (C₄-arom.),127.01 (C_(2,6)H-arom.), 125.43 (C₇H-arom.), 118.69 (C₁₅H-arom.), 116.38(C₁₄H- arom.), 114.10 (C₈-arom.), 113.76 (C_(3,5)H-arom.), 55.01(C₁₇H₃).

6-(7-methyl-1H-indol-3-yl)isoquinoline (Procedure 10)

VPC Number LabBook Code IC₅₀ (eGFP) = inactive 13765 CA 4-128Precipitate (yield = 34%) IC₅₀ (PSA) = inactive

t_(R) (HPLC) = 3.01 min MS (ESI+) m/z = 259.1230 [(M + H)⁺] Mp =222-225° C. HRMS (ESI+): calculated for C₁₈H₁₅N₂, m/z = 259.1230; found,259.1231 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.59 (s, 1H, H₅), 9.25(s, 1H, H₁₆), 8.47 (d, J = 5.7 Hz, 1H, H₁₂), 8.27 (s, 1H, H₁₇),8.15-8.09 (m, 2H, H_(19,20)), 8.01 (d, J = 2.7 Hz, 1H, H₄), 7.95 (d, J =8.0 Hz, 1H, H₉), 7.88 (d, J = 5.8 Hz, 1H, H₁₃), 7.11 (t, J = 7.5 Hz, 1H,H₉), 7.03 (d, J = 7.0 Hz, 1H, H₇), 2.54 (s, 3H, H₁₀). ¹³C NMR (151 MHz,DMSO-d₆): δ (ppm) = 151.69 (C₁₆H-arom.), 143.10 (C₁₂-arom.), 138.20(C₁₈-arom.), 136.65 (C₁-arom.), 136.13 (C₁₄-arom.), 127.81 (C₂₀H-arom.),127.20 (C₁₉H-arom.), 126.42 (C₁₅-arom.), 125.23 (C₄H-arom.), 124.55(C₂-arom.), 122.35 (C₇H-arom.), 121.35 (C₆- arom.), 121.17 (C₁₇H-arom.),120.35 (C₈H-arom.), 120.20 (C₁₃H- arom.), 116.98 (C₉H-arom.), 115.17(C₃-arom.), 16.81 (C₁₀H₃).

2-(6-fluoro-1H-indol-3-yl)quinoline

LabBook Code VPC Number CA 4-131 F25-28 Precipitate IC₅₀ (eGFP) = 0.113764 (yield = 5%) IC₅₀ (PSA) = 0.082

t_(R) (HPLC) = 3.07 min MS (ESI+) m/z = 263.0968 [(M + H)⁺] Mp =195-198° C. HRMS (ESI+): calculated for C₁₇H₁₂FN₂, m/z = 263.0979;found, 263.0981 ¹H NMR (600 MHz, DMSO-d₆): δ (ppm) = 11.71 (s, 1H, H₁₇),8.90 (dd, J = 8.7, 5.9 Hz, 1H, H₁₆), 8.36 (d, J = 2.6 Hz, 1H, H₁₈), 8.27(d, J = 8.7 Hz, 1H, H₁₀), 8.06-8.02 (m, 2H, H_(3,9)), 7.90 (d, J = 7.7Hz, 1H, H₆), 7.72 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H, H₆), 7.49 (ddd, J =7.8, 6.6, 0.6 Hz, 1H, H₁), 7.26 (dd, J = 9.8, 2.4 Hz, 1H, H₁₃), 7.07(td, J = 9.6, 2.4 Hz, 1H, H₁₁). ¹³C NMR (151 MHz, DMSO-d₆): δ (ppm) =159.13 (d, J = 235.8 Hz, C₁₂- arom.), 155.18 (C₈-arom.), 147.68(C₄-arom.), 137.16 (d, J = 12.5 Hz, C₁₄- arom.), 135.69 (C₁₀H-arom.),129.38 (C₂H-arom.), 128.39 (C₃H-arom.), 128.32 (d, J = 2.8 Hz,C₁₈H-arom.), 127.63 (C₆H-arom.), 125.87 (C₅-arom.), 125.02 (C₁H-arom.),123.78 (d, J = 9.8 Hz, C₁₆H-arom.), 122.40 (C₁₅-arom.), 119.08(C₉H-arom.), 115.58 (C₁₉-arom.), 108.64 (d, J = 23.6 Hz, C₁₁H-arom.),97.73 (d, J = 25.4 Hz, C₁₃H-arom.).A person of skill in the art based on the general knowledge in the artand the information provided herein would be able to synthesize thecompounds described herein or modify the compounds described herein.eGFP Cellular Transcription AssayAR transcriptional activity was assayed as previously described(Tavassoli, P. et al. Rapid, non-destructive, cell-based screeningassays for agents that modulate growth, death, and androgen receptoractivation in prostate cancer cells. Prostate 2007, 67, 416-426).Briefly, stably transfected eGFP-expressing LNCaP human prostate cancercells (LN-ARR2PB-eGFP) containing an androgen responsiveprobasin-derived promoter (ARR2PB) were grown in phenol red free RPMI1640 supplemented with 5% CSS. After 5 days, the cells were plated intoa 96-well plate (35,000 cells/well) with 0.1 nM of the syntheticandrogen R1881 and increasing concentrations (0-100 μM) of compound. Thecells were incubated for three days and the fluorescence was thenmeasured (excitation 485 nm, emission 535 nm). The viability of thesecells was assayed by MTS cell proliferation assay (CellTiter 961™Aqueous One Solution Reagent, Promega™).Structure Solution and RefinementThe ternary complex structure was solved by molecular replacement usingthe Phaser program (McCoy, A. J. et al. Phaser crystallographicsoftware. J Appl Crystallogr 2007, 40, 658-674) and the coordinate of anapo-protein structure of AR-testosterone complex (Protein Data Bankentry 2AM9) as the search model. The structures were refined withiterative cycles of manual density fitting with COOT and refinement withRefmac (Murshudov, G. N. et al. Refinement of macromolecular structuresby the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr.1997, 53, 240-255). The extra density of testosterone was clearlyobserved at the initial refinement step. A characteristic electrondensity of the compound was observed at the BF3 binding site.Heterologous Expression of Androgen ReceptorThe AR ligand binding domain was expressed and purified as previouslydescribed (Estebanez-Perpina, E. et al. Proc. Nat. Acad. Sci. USA (2007)104:16074-16079).eGFP Cellular AR Transcription Assay:AR transcriptional activity was assayed as previously described.²¹Briefly, stably transfected eGFP-expressing LNCaP human prostate cancercells (LN-ARR2PBeGFP) containing an androgen-responsive probasin-derivedpromoter (ARR2PB) were grown in phenol-red-free RPMI 1640 supplementedwith 5% CSS. After 5 days, the cells were plated into a 96-well plate(35,000 cells/well) with 0.1 nM R1881 and increasing concentrations(0-100 μM) of compound. The cells were incubated for 3 days, and thefluorescence was then measured (excitation, 485 nm; emission, 535 nm).The viability of these cells has been assayed by the MTS cellproliferation assay (CellTiter 961 Aqueous One Solution Reagent,Promega) according to the instructions of the manufacturer.Prostate Surface Antigen Assay:The evaluation of PSA excreted into the media was performed in parallelto the eGFP assay using the same plates (see above description). Afterthe cells were incubated for 3 days 150 μl of the media was taken fromeach well, and added to 150 μl of PBS. PSA levels were then evaluatedusing Cobase 411 analyzer instrument (Roche Diagnostics) according tothe manufacturer's instructions.

EXAMPLES Example 1—Virtual Screen for Potential BF3 Binders

Using a previously described (Axerio-Cilies, P. et al. Inhibitors ofAndrogen Receptor Activation Function-2 (AF2) Site Indentified ThroughVirtual Screening. J Med Chem 2011 54(18):6197-205), consensus-based insilico methodology we conducted a virtual screen of ˜10 millionpurchasable chemical substances from the ZINC database to identifyBF3-specific binders (also one NCI compound). The screening method useda combination of large-scale docking, ligand-based QSAR modeling,pharmacophore search, molecular field analysis, molecular-mechanic andmolecular dynamic simulations (Cherkasov, A. et al. Progressive docking:a hybrid QSAR/docking approach for accelerating in silico highthroughput screening. J Med Chem. 2006, 49, 7466-7478; Cherkasov, A. etal. ‘Inductive’ charges on atoms in proteins: comparative docking withthe extended steroid benchmark set and discovery of a novel SHBG ligand.J Chem Inf Model 2005, 45, 1842-1853; and Santos-Filho, O. A. andCherkasov, A. Using molecular docking, 3D-QSAR, and cluster analysis forscreening structurally diverse data sets of pharmacological interest. JChem Inf Model 2008, 48, 2054-2065). The results from each stage of thismulti-parametric approach were compiled and the compounds were rankedusing a consensus scoring procedure. The highest ranked compounds werevisualized and initial candidates, predicted to have a high potentialfor binding to the BF3 pocket, were selected for empirical testing.

Example 2—Cell-Based Testing

All compounds were screened for their ability to inhibit ARtranscriptional activity using a non-destructive, cell-based eGFPscreening assay (Tavassoli, P. et al. Rapid, non-destructive, cell-basedscreening assays for agents that modulate growth, death, and androgenreceptor activation in prostate cancer cells. Prostate 2007, 67,416-426). In this assay, the expression of eGFP is under the control ofan androgen responsive probasin-derived promoter and can quantify ARtranscriptional activity. From the compounds tested, 7 showed sub-μMIC50 values in the eGFP assay. Compounds that exhibited non-specificcellular toxicity were removed from further analysis. The most potentmolecules had IC₅₀'s ranging in from 0.11 to 50 μM range (TABLE 3). Somecompounds were also tested in the PSA assay (TABLE 3).

TABLE 3 Structural and experimental data for the AR BF₃ interactors.eGFP Internal ZINC IC₅₀ PSA IC₅₀ Number Number STRUCTURE (μM) (μM) 13555Synthetic derivative

Inactive Not tested 13557 Synthetic derivative

Inactive Not tested  9039 Synthetic derivative

>200   Not tested 13312 ZINC00298052

200.0  Not tested  9040 Synthetic derivative

39.13 Not tested 13309 ZINC01234071

27.2  Not tested  9034 Synthetic derivative

20  Not tested 13551 Synthetic derivative

15.5  Not tested 13550 Synthetic derivative

11.75 Not tested  9026 Synthetic derivative

11.67 Not tested 13544 Synthetic derivative

11.4  13561 Synthetic derivative

10.7  Not tested 13310 ZINC00297221

10.3  Not tested 13232 ZINC02992016

10  Not tested  9028 Synthetic derivative

10  Not tested 13050 ZINC03365783

 9.725 Not Determined 13300 ZINC00270867

9.3  6.76 13299 ZINC00499454

8.2 Not tested  9027 Synthetic derivative

 7.721 Not tested 13538 Synthetic derivative

7.7 13304 ZINC00270887

7.3  4.54 13258 ZINC18191564

6.8 Not tested 13559 Synthetic derivative

6.6 Not tested 13512 Synthetic derivative

6.0 13542 Synthetic derivative

5.7  9125 ZINC30469682

5.2 2.4 13186 ZINC00513042

5  Not determined 13224 ZINC04106386

5  Not determined 13524 Synthetic derivative

4.9  6.65 13508 Synthetic derivative

4.8 2.7 13250 ZINC03149578

4.7 Not tested 13530 Synthetic derivative

4.7  1.60 13303 ZINC00270884

4.5 Not tested 13503 Synthetic derivative

4.5 Not tested 13257 ZINC12345945

4.2 Not tested 13502 Synthetic derivative

4.1 Not tested  9037 Synthetic derivative

 4.093 Not tested 13243 ZINC00253227

3.9 Not tested 13543 Synthetic derivative

3.7  3.19 13424 ZINC12346351

3.7  3.58 13516 Synthetic derivative

3.6 Not tested  6054 ZINC08718421

3.4 Not Determined 13505 Synthetic derivative

3.4 Not tested 13522 Synthetic derivative

3.4  2.19 13029 ZINC00210926

 3.221 Not Determined 13548 Synthetic derivative

 3.21  4.24  9128 ZINC47424036

3.2 3.5 13525 Synthetic derivative

3.1  7.09 13511 Synthetic derivative

3.0 1.9 13216 ZINC06025409

2.8 Not Determined 13532 Synthetic derivative

2.8  3.10 13260 ZINC4941101

2.7 Not tested 13416 ZINC01869964

2.7  2.32 13509 Synthetic derivative

2.6 3.1  9043 Synthetic derivative

 2.503 Not tested 13202 ZINC01768344

2.5 Not Determined 13510 Synthetic derivative

2.5  1.54 13540 Synthetic derivative

2.5 Not tested 13411 ZINC04106386

2.4 2.4 13560 Synthetic derivative

2.3 7.5 13214 ZINC26472877

2.2 Not Determined 13235 ZINC01037115

2.2  1.01 13536 Synthetic derivative

2.2  2.521 13556 Synthetic derivative

 2.112  2.18 13127 ZINC00392643

2.1  0.11 13261 ZINC48546225

2.1 Not tested 13215 ZINC05504717

2  Not Determined 13504 Synthetic derivative

2.0  1.69 13167 NSC105329

1.9  1.25 13206 ZINC04962047

1.8 Not Determined 13145 ZINC34603778

1.7  2.46 13549 Synthetic derivative

1.7  2.57 13245 ZINC00555700

1.7  1.69 13036 ZINC14961821

 1.602 Not Determined 13166 ZINC01723993

1.6  2.12 13558 Synthetic derivative

1.6 2.1 13535 Synthetic derivative

1.5  1.873 13164-B ZINC02046058

1.3  1.59 13500 Synthetic derivative

 1.23  0.41 13254 ZINC18191551

1.2 Not tested 13410 ZINC04106383

1.2  2.03 13552 Synthetic derivative

 1.125  1.14 13423 ZINC18191568

1.1 1.2 13222 ZINC02718340

 0.95  0.74 13247 ZINC48090221

0.9  0.43 13412 ZINC02718340

0.9  1.23 13534 Synthetic derivative

0.8  1.251 13434 ZINC00069102

0.8  0.73 13164-A ZINC02046058

 0.77  0.67 13220 ZINC48544111

0.7 Not Determined 13225 ZINC18191568

0.7 0.9 13537 Synthetic derivative

0.7   0.8057 13436 ZINC00068959

0.6 0.4 13554 Synthetic derivative

 0.59  0.67 13541 Synthetic derivative

0.5  0.94 13255 ZINC18191553

0.5  0.46 13163-A ZINC02043019

 0.48  0.16 13163-B ZINC02043019

 0.48  0.24 13256 ZINC05848672

0.4  0.13 13521 Synthetic derivative

0.4  0.26 13427 ZINC00588219

0.4  0.31 13259 ZINC18191559

0.3  0.25 13506 Synthetic derivative

 0.18 0.6 13226 ZINC18191571

 0.11  0.076 13562 Known see U.S. Pat. No. 6,207,679

 0.06  0.14 13566 Known see U.S. Pat. No. 6,207,679

 0.004  0.011 13567 Synthetic derivative

 0.200  0.230 13568 Synthetic derivative

 1.300  1.560 13569 Synthetic derivative

 1.600 Not tested 13570 Synthetic derivative

 20.000 Not tested 13571 Synthetic derivative

 1.100 Not tested 13573 Synthetic derivative

 0.560 Not tested 13574 Synthetic derivative

 2.570 Not tested 13576 Synthetic derivative

 0.144  0.048 13577 Synthetic derivative

 3.200  1.730 13579 Synthetic derivative

 0.101  0.043 13580 Synthetic derivative

 2.900 Not tested 13582 Synthetic derivative

 0.052  0.041 13585 Synthetic derivative

 0.110  0.039 13587 Synthetic derivative

 0.760  0.530 13589 Synthetic derivative

 5.300 Not tested 13591 Synthetic derivative

 0.042  0.085 13592 Synthetic derivative

 1.590  1.220 13593 Synthetic derivative

 0.198  0.130 13594 Synthetic derivative

 0.166  0.099 13595 Synthetic derivative

 0.177 Not tested 13596 Synthetic derivative

Inactive Inactive 13597 Synthetic derivative

 0.236  0.132 13598 Synthetic derivative

Inactive Inactive 13599 Synthetic derivative

Inactive Inactive 13600 Synthetic derivative

 1.249  0.929 13601 Synthetic derivative

 0.233  0.165 13602 Synthetic derivative

 0.240  0.182 13603 Synthetic derivative

 0.633  0.339 13604 Synthetic derivative

Inactive Inactive 13605 Synthetic derivative

Inactive Inactive 13606 Synthetic derivative

 1.649  1.427 13607 Synthetic derivative

 0.168  0.087 13608 Synthetic derivative

Inactive Inactive 13609 Synthetic derivative

Inactive Inactive 13610 Synthetic derivative

 0.032  0.013 13611 Synthetic derivative

 0.297  0.121 13612 Synthetic derivative

 1.44  0.813 13613 Synthetic derivative

 11.540  1.738 13614 Synthetic derivative

 1.117  0.597 13615 Synthetic derivative

Inactive Inactive 13616 Synthetic derivative

Inactive Inactive 13617 Synthetic derivative

Inactive Inactive 13618 Synthetic derivative

 0.194  0.13 13619 Synthetic derivative

 2.170 Not tested 13620 Synthetic derivative

Inactive Inactive 13621 Synthetic derivative

 0.02  0.008 13622 Synthetic derivative

0.1  0.075 13623 Synthetic derivative

Inactive Inactive 13624 Synthetic derivative

 0.100  0.042 13625 Synthetic derivative

 1.900  1.230 13626 Synthetic derivative

 2.700  1.650 13627 Synthetic derivative

 1.500  1.160 13628 Synthetic derivative

 0.800  0.610 13629 Synthetic derivative

 4.900  1.780 13630 Synthetic derivative

 0.600  0.430 13631 Synthetic derivative

Inactive Inactive 13632 Synthetic derivative

Inactive Inactive 13633 Synthetic derivative

 6.000 Not tested 13634 Synthetic derivative

 5.000 Not tested 13635 Synthetic derivative

Inactive Inactive 13636 Synthetic derivative

Inactive Inactive 13637 Synthetic derivative

Inactive Inactive 13638 Synthetic derivative

Inactive Inactive 13639 Synthetic derivative

 0.549  0.544 13640 Synthetic derivative

 12.670 Not tested 13641 Synthetic derivative

 0.132  0.403 13642 Synthetic derivative

 0.033  0.025 13643 Synthetic derivative

  0.1638  0.156 13644 Synthetic derivative

 3.000 Not tested 13645 Synthetic derivative

 0.261  0.247 13646 Synthetic derivative

 0.179  0.224 13647 Synthetic derivative

Inactive Inactive 13648 Synthetic derivative

Inactive Inactive 13649 Synthetic derivative

Inactive Inactive 13650 Synthetic derivative

 1.631 Not tested 13651 Synthetic derivative

 0.404 Not tested 13652 Synthetic derivative

 3.54  1.76 13653 Synthetic derivative

 1.13  0.29 13654 Synthetic derivative

 0.92  0.16 13655 Synthetic derivative

 1.66  0.61 13656 Synthetic derivative

 0.99  0.46 13657 Synthetic derivative

Inactive Inactive 13658 Synthetic derivative

 2.85  2.21 13659 Synthetic derivative

Inactive Inactive 13660 Synthetic derivative

2.5  1.89 13661 Synthetic derivative

Inactive Inactive 13662 Synthetic derivative

Inactive Inactive 13663 Synthetic derivative

Inactive Inactive 13664 Synthetic derivative

Inactive Inactive 13665 Synthetic derivative

 0.27  0.21 13666 Synthetic derivative

Inactive Inactive 13667 Synthetic derivative

Inactive Inactive 13668 Synthetic derivative

Inactive Inactive 13669 Synthetic derivative

Inactive Inactive 13670 Synthetic derivative

Inactive Inactive 13671 Synthetic derivative

Inactive Inactive 13672 Synthetic derivative

Inactive Inactive 13673 Synthetic derivative

Inactive Inactive 13674 Synthetic derivative

 0.075  0.051 13677 Synthetic derivative

 0.156  0.11 13678 Synthetic derivative

Inactive Inactive 13679 Synthetic derivative

Inactive Inactive 13680 Synthetic derivative

0.8 Not tested 13681 Synthetic derivative

2.5 1.7 13682 Synthetic derivative

 0.89  0.99 13683 Synthetic derivative

2.6  1.906 13684 Synthetic derivative

1.4  6.609 13685 Synthetic derivative

Inactive Inactive 13686 Synthetic derivative

Inactive Inactive 13687 Synthetic derivative

Inactive Inactive 13688 Synthetic derivative

 0.069  0.068 13689 Synthetic derivative

Inactive Inactive 13690 Synthetic derivative

Inactive Inactive 13691 Synthetic derivative

0.4  0.48 13692 Synthetic derivative

0.1  0.082 13693 Synthetic derivative

 0.11  0.12 13694 Synthetic derivative

 0.07  0.067 13695 Synthetic derivative

 0.069  0.087 13696 Synthetic derivative

 0.042  0.042 13697 Synthetic derivative

 0.029  0.029 13698 Synthetic derivative

 0.041  0.041 13699 Synthetic derivative

 0.073  0.073 13700 Synthetic derivative

Inactive Inactive 13701 Synthetic derivative

Inactive Inactive 13702 Synthetic derivative

 0.21  0.14 13704 Synthetic derivative

 0.35  0.169 13705 Synthetic derivative

Inactive Inactive 13706 Synthetic derivative

Inactive Inactive 13707 Synthetic derivative

Inactive Inactive 13708 Synthetic derivative

 0.29  0.29 13709 Synthetic derivative

Inactive Inactive 13710 Synthetic derivative

 0.23  0.25 13711 Synthetic derivative

Inactive Inactive 13712 Synthetic derivative

Inactive Inactive 13713 Synthetic derivative

 0.037 13714 Synthetic derivative

Inactive Inactive 13717 Synthetic derivative

 0.49  0.33 13718 Synthetic derivative

 0.37  0.11 13719 Synthetic derivative

 0.11  0.13 13720 Synthetic derivative

Inactive Inactive 13721 Synthetic derivative

Inactive Inactive 13722 Synthetic derivative

Inactive Inactive 13723 Synthetic derivative

Inactive Inactive 13724 Synthetic derivative

Inactive Inactive 13725 Synthetic derivative

Inactive Inactive 13726 Synthetic derivative

Inactive Inactive 13727 Synthetic derivative

Inactive Inactive 13728 Synthetic derivative

Inactive Inactive 13729 Synthetic derivative

Inactive Inactive 13730 Synthetic derivative

 0.149  0.198 13731 Synthetic derivative

 0.304  0.255 13732 Synthetic derivative

 0.42 Not tested 13733 Synthetic derivative

 3.815   0.9194 13736 Synthetic derivative

 0.62  0.68 13738 Synthetic derivative

 0.083  0.062 13741 Synthetic derivative

 0.29  0.29 13742 Synthetic derivative

 0.22 0.2 13743 Synthetic derivative

 0.38  0.39 13744 Synthetic derivative

 0.76  0.75 13745 Synthetic derivative

 1.01  0.95 13746 Synthetic derivative

Inactive Inactive 13747 Synthetic derivative

Inactive Inactive 13748 Synthetic derivative

Inactive Inactive 13749 Synthetic derivative

 0.29  0.22 13750 Synthetic derivative

Inactive Inactive 13751 Synthetic derivative

Inactive Inactive 13752 Synthetic derivative

 0.37  0.26 13753 Synthetic derivative

 0.16  0.098 13754 Synthetic derivative

 0.09  0.051 13755 Synthetic derivative

 0.47  0.47 13757 Synthetic derivative

Inactive Inactive 13758 Synthetic derivative

Inactive Inactive 13759 Synthetic derivative

0.3  0.27 13760 Synthetic derivative

0.1  0.052 13761 Synthetic derivative

  0.5481   0.3829 13762 Synthetic derivative

  0.4792  0.429 13764 Synthetic derivative

0.1  0.082 13765 Synthetic derivative

Inactive Inactive 13766 Synthetic derivative

 0.045  0.020 13769 Synthetic derivative

Inactive Inactive 13770 Synthetic derivative

0.1  0.017 13771 Synthetic derivative

0.2  0.090 13772 Synthetic derivative

0.2  0.172 13773 Synthetic derivative

0.3  0.303 13774 Synthetic derivative

0.7  0.773 13775 Synthetic derivative

3.7 Not tested 13776 Synthetic derivative

 0.21  0.19 13777 Synthetic derivative

Not tested Not tested 13778 Synthetic derivative

Not tested Not tested 13779 Synthetic derivative

Not tested Not tested 13780 Synthetic derivative

Not tested Not tested 13781 Synthetic derivative

Not tested Not tested 13782 Synthetic derivative

 0.11 Not tested 13783 Synthetic derivative

Not tested Not tested 13784 Synthetic derivative

Not tested Not tested 13785 Synthetic derivative

 0.036 Not tested 13786 Synthetic derivative

 0.013 Not tested 13787 Synthetic derivative

 0.19 Not tested 13788 Synthetic derivative

Not tested Not tested 13507 Synthetic derivative

Not tested Not tested 13513 Synthetic derivative

Not tested Not tested 13514 Synthetic derivative

Not tested Not tested 13515 Synthetic derivative

Not tested Not tested 13517 Synthetic derivative

Not tested Not tested 13518 Synthetic derivative

Not tested Not tested 13519 Synthetic derivative

Not tested Not tested 13520 Synthetic derivative

Not tested Not tested 13523 Synthetic derivative

Not tested Not tested 13526 Synthetic derivative

Not tested Not tested 13527 Synthetic derivative

Not tested Not tested 13531 Synthetic derivative

Not tested Not tested 13539 Synthetic derivative

Not tested Not tested 13545 Synthetic derivative

Not tested Not tested 13546 Synthetic derivative

Not tested Not tested 13547 Synthetic derivative

Not tested Not testedWhere a compound is described as “inactive”, no activity was detectedfor the compound in the assays on which it was tested.

Although various embodiments of the invention are disclosed herein, manyadaptations and modifications may be made within the scope of theinvention in accordance with the common general knowledge of thoseskilled in this art. Such modifications include the substitution ofknown equivalents for any aspect of the invention in order to achievethe same result in substantially the same way. Numeric ranges areinclusive of the numbers defining the range. The word “comprising” isused herein as an open-ended term, substantially equivalent to thephrase “including, but not limited to”, and the word “comprises” has acorresponding meaning. As used herein, the singular forms “a”, “an” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a thing” includes more thanone such thing. Citation of references herein is not an admission thatsuch references are prior art to an embodiment of the present invention.The invention includes all embodiments and variations substantially ashereinbefore described and with reference to the examples and drawings.

What is claimed is:
 1. A compound having the structure of Formula I:

wherein,

is either a single or a double bond between D₂ and D₃; A₁ is F, Br orCl; A₂ is H, Br, OH, Cl, F, I, CH₃, NH₂, OCH₃ or CF₃; A₃ is H, Br, NH₂,F, Cl, CH₃ or CF₃; A₄ is H, Br, Cl, F, I, CH₃ or CF₃; D₁ is

wherein E₃₇ is NH; D₂ is

G₁ is CH; D₃ is


2. The compound of claim 1, wherein the compound is selected from one ormore of:


3. The compound of claim 1, wherein

is a double bond between D₂ and D₃; A₁ is F, Br or Cl; A₂ is H, Br, OH,Cl, F, I, CH₃, NH₂, OCH₃ or CF₃; A₃ is H, Br, NH₂, F, Cl, CH₃ or CF₃;and A₄ is H, Br, Cl, F, I, CH₃ or CF₃.
 4. The compound of claim 1,wherein

is a double bond between D₂ and D₃; A₂ is H, Br, Cl, F, I, CH₃, NH₂,OCH₃ or CF₃; A₃ is II, Br, NH₂, F, Cl or CH₃; and A₄ is H, Br, Cl, F, Ior CH₃.
 5. The compound of claim 1, wherein

is a double bond between D₂ and D₃; A₂ is H, Br, Cl, F, 1, CH₃, NH₂ orOCH₃; A₃ is H, Br, F, Cl, CH₃ or CF₃; and A₄ is H, Br Cl, F, I or CF₃.6. The compound of claim 1, wherein

is a double bond between D₂ and D₃; A₂ is H, Br, Cl, F, I, CH₃ or NH₂;A₃ is H, Br, F, Cl, or CH₃; and A₄ is H, Br, Cl, F or I.
 7. The compoundof claim 1, wherein

is a double bond between D₂ and D₃; A₂ is H, Br, Cl, F, I or CH₃; A₃ isH, Br, F, Cl or CH₃; and A₄ is H, Br, Cl or F.
 8. The compound of claim1, wherein

is a double bond between D₂ and D₃; A₂ is H, F, or CH₃; A₃ is H, F, Clor CH₃; and A₄ is H, Cl or F.
 9. The compound of claim 1, wherein thecompound has the structure of Formula II:

wherein, L₁ is H; L₂ is H; L₃ is H; L₄ is H; L₅ is H; L₆ is H; L₇ is H,F, Cl or Br; L₈ is H, Cl, F, Br, NH₂, or CH₃; L₉ is H, Cl, F, Br, OH,NH₂, OCH₃, or CH₃; and L₁₀ is Cl, F or Br.
 10. The compound of claim 9,wherein L₇ is H, F or Cl; L₈ is H, Cl, F or CH₃; L₉ is H, Cl, F or CH₃;and L₁₀ is Cl, F or Br.
 11. The compound of claim 9, wherein thecompound is:


12. A pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof according to claim 1 and apharmaceutically acceptable excipient.
 13. The pharmaceutical of claim12, wherein the compound has the structure of Formula II:

wherein, L₁ is H; L₂ is H; L₃ is H; L₄ is H; L₅ is H; L₆ is H; L₇ is H,F, Cl or Br; L₈ is H, Cl, F, Br, NH₂, or CH₃; L₉ is H, Cl, F, Br, OH,NH₂, OCH₃, or CH₃; and L₁₀ is Cl, F or Br; or pharmaceuticallyacceptable salt thereof.
 14. A method of treating prostate cancer, themethod comprising administering a compound of claim 1 to a subject inneed of said treatment.
 15. The method of claim 14, wherein the compoundis:


16. The method of claim 14, wherein

is a double bond between D₂ and D₃; A₁ is F, Br or Cl; A₂ is H, Br, OH,Cl, F, I, CH₃, NH₂, OCH₃ or CF₃; A₃ is H, Br, NH₂, F, Cl, CH₃ or CF₃;and A₄ is H, Br, Cl, F, I, CH₃ or CF₃.
 17. The method of claim 14,wherein

is a double bond between D₂ and D₃; A₂ is H, Br, Cl, F, I, CH₃, NH₂,OCH₃ or CF₃; A₃ is H, Br, NH₂, F, Cl or CH₃; and A₄ is H, Br, Cl, F, Ior CH₃.
 18. The method of claim 14, wherein

is a double bond between D₂ and D₃; A₂ is H, Br, Cl, F, I, CH₃, NH₂ orOCH₃; A₃ is II, Br, F, Cl, CH₃ or CF₃; and A₄ is H, Br, Cl, F, I or CF₃.19. The method of claim 14, wherein

is a double bond between D₂ and D₃; A₂ is H, Br, Cl, F, I, CH₃ or NH₂;A₃ is H, Br, F, Cl, or CH₃; and A₄ is H, Br, Cl, F or I.
 20. The methodof claim 14, wherein

is a double bond between D₂ and D₃; A₂ is H, Br, Cl, F, I or CH₃; A₃ isH, Br, F, Cl or CH₃; and A₄ is H, Br, Cl or F.
 21. The method of claim14, wherein

is a double bond between D₂ and D₃; A₂ is H, F, or CH₃; A₃ is H, F, Clor CH₃; and A₄ is H, Cl or F.
 22. The method of claim 14, wherein thecompound has the structure of Formula II:

wherein, L₁ is H; L₂ is H; L₃ is H; L₄ is H; L₅ is H; L₆ is H; L₇ is H,F, Cl or Br; L₃ is H, Cl, F, Br, NH₂, or CH₃; L₉ is H, Cl, F, Br, OH,NH₂, OCH₃, or CH₃; and L₁₀ is Cl, F or Br.
 23. The method of claim 22,wherein L₇ is H, F or Cl; L₈ is H, Cl, F or CH₃; L₉ is H, Cl, F or CH₃;and L₁₀ is Cl, F or Br.
 24. The method of claim 22, wherein the compoundis: